Role of Proteases in the Pathophysiology of Neurodegenerative Diseases

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J Cell Biol Am J Pathol J Neurochem Suppl 1: Crit Rev Oncol Hematol Nat Cell Biol Hum Mol Genet A triple threat in the regulation of the neuronal cytoskeleton. Mol Cell Neurosci J Aging Res Curr Opin Cell Biol Cell Mol Life Sci Nat Rev Neurosci Ageing Res Rev Med Res Rev J Parkinsons Dis 7: Am J Hum Genet How to cite this article: Neural Regen Res ; How to cite this URL: CatD and Calcineurin in PD.

CatD, Calcineurin and the Retromer: Interplay of cathepsin D CatD , calcineurin and the retromer in health and neurodegenerative diseases. These mutations do not affect the localization of the protein, but instead affect its proteolytic activity, resulting in increased mitochondrial susceptibility Strauss et al. Mice lacking HTRA2 expression develop a specific neurodegeneration of striatal neurons together with a parkinsonian phenotype akinetic and rigid syndrome, showing a lack of coordination, decreased mobility and tremor leading to early death, thus challenging the notion that HTRA2 is a major regulator of apoptotic cell death Martins et al.

HTRA2 phosphorylation increases its proteolytic activity in a PINK1-dependent manner, suggesting that these proteins might be part of the same stress-sensing pathway Plun-Favreau et al. Huntingtin fragments have been reported to be in close apposition to mitochondria in cellular and animal models of HD Gutekunst et al. Localization of mutant huntingtin to brain mitochondria from mouse has been reported to impair protein import through the interaction with TIM23 complex.

Importantly, mutant huntingtin association with TIM23 complex was not present with wild-type huntingtin, suggesting a role for polyglutamine domains in the interaction Figure 3. The rescue of mitochondrial protein import by lentiviral delivery of Tim23, Tim50, and Tim17a, prevented mitochondrial dysfunction and cell death in mutant huntingtin-expressing neurons Yano et al. The presence of mutant huntingtin with polyglutamine repeats also seems to impair the mitochondrial disulfide relay system MDRS in mouse striatal cells.

Specifically, Napoli et al. This deficit was concomitant with the presence of a disrupted mitochondrial morphology, lower mtDNA copy number and increased deletions, lower complex I, IV, and V activities, decreased ATP production and increased oxidative stress Napoli et al.

This suggests that an initial deficit in MDRS could lead to an altered downstream import pathway Figure 3. However, the reported study presents some limitations such as the use of only in vitro models and the absence of any mechanistic description. Interestingly, this mutation leads to specific degeneration of striatal neurons Jones et al.

In a study comparing the gene expression profiles of three types of neurons expressing wild-type or mutant huntingtin, HTRA2 mRNA was specifically downregulated only in striatal neurons with mutant huntingtin Tagawa et al. Moreover, the overexpression of HTRA2 in primary neurons protected against mutant huntingtin-induced cell death, while the suppression of HTRA2 renders those neurons susceptible to mutant huntingtin.

These data suggest that the selective reduction of HTRA2 in striatal neurons could be linked to their selective vulnerability in HD pathology Inagaki et al. While it is clear that proteostasis is altered in HD, it remains uncertain whether the aggregates present are the main mediators of neuronal dysfunction. Those aggregates can have a dual role, on one hand sequestering the toxic protein, but on the other, acting as a hub to incorporate several proteins.

While molecular chaperones are the first line of defense against protein aggregates, expression of expanded polyglutamine peptides leads to impaired protein folding capacity. However, no specific alteration in mitochondrial molecular chaperones has been reported so far in the context of HD. As discussed above, the mitochondrial proteome is encoded by both mitochondrial and nuclear DNA. Proteostatic stress can arise for a variety of reasons: Mitochondria have developed their own mechanisms such as the one present in the endoplasmic reticulum, ER to respond to this proteostatic stress, called the mitochondrial Unfolded Protein Response mtUPR.

This response is a mechanism of mitochondrial to nucleus communication Martinus et al. The first characterization was made in mammalian cells and uncovered a transcriptional response characterized by the upregulation of nuclear genes encoding for mitochondrial chaperones HSP60, HSP10, mtDnaJ and CLPP protease Zhao et al. However, the following studies have used C. One of the suggested models for mtUPR activation in C. ATFS-1 has also a nuclear localization signal and upon mtUPR activation, its trafficking to mitochondria is impaired, leading to its translocation into the nucleus and subsequent transcriptional activation of several genes that are protective against mitochondrial dysfunction Nargund et al.

Therefore, ATFS-1 functions as a sensor of mitochondrial import efficiency, implying that any condition that hampers mitochondrial protein import activity could potentially activate mtUPR Chacinska et al. While the mtUPR has been extensively investigated in C. Importantly, in response to mitochondrial stress in both C. In summary, mtUPR is emerging as a stress response pathway, which coordinates two different compartments, the nuclear and the mitochondrial, to promote mitochondrial health.

A reduction in protein synthesis, which is one of the consequences of mtUPR activation, rescues many of the defects in flies lacking PINK1 Liu and Lu, , while Drosophila flies overexpressing a mutant OTC ornithine transcarbamylase protein prone to aggregation develop mitochondrial dysfunction phenotypes similar to PINK1 and Parkin mutants Pimenta de Castro et al.

To this end, analysis of post-mortem brains from PD patients carrying PINK1 mutations revealed enhanced levels of misfolded components of the mitochondrial respiratory chain as well as increased levels of the mtUPR marker of activation HSP60 Pimenta de Castro et al. In mice, deletion of HTRA2 results in the accumulation of unfolded proteins in the mitochondria and leads to neurodegeneration Moisoi et al.

The mtUPR pathway is generally regarded as beneficial for cellular homeostasis, especially in response to genetic or environmental challenges; however, some reports have started to challenge this view, indicating that the mtUPR pathway could be detrimental to the cell under some circumstances. Recently, Martinez et al. Importantly, overexpression and overactivation of ATFS-1 over time, which lead to mtUPR signaling, was found to be detrimental and to induce neurodegeneration in C.

Taken together, while these observations challenge the mainstream view of mtUPR as a protective pathway, more studies are needed to fully understand the role of mtUPR in the context of PD. However, given the discovery that mutant huntingtin is able to block mitochondrial protein import, which is thought to be, at least in C. Mitochondria are dynamic organelles whose structure varies constantly from a tubular network to individual mitochondria. This mitochondrial network is controlled by the balance between various regulated processes: While mitochondrial fusion is believed to favor mitochondrial biogenesis by the exchange of new proteins and mtDNA between the merging organelles, mitochondrial fission is considered to be a process that isolates dysfunctional mitochondria so that they can be cleared by mitophagy.

Mitochondrial fusion and fission control mitochondrial number and size. Fission is mediated by dynamin-related protein 1 Drp1 and mitochondrial fission-1 protein Fis1. Mitofusins Mnf 1 and 2 are involved in the fusion of the outer membrane, whereas protein optic atrophy type 1 OPA1 regulates the fusion of the inner membrane. Mitochondrial biogenesis is the process by which cells increase their individual mitochondrial mass to increase the production of ATP as a response to greater energy demand.

In neurons, mitochondria are recruited to subcellular compartments distant from the cell body, such axons and dendrites, by active transport along microtubules and actin filaments. Selective autophagic degradation of mitochondria i. When mitochondrial deterioration is mild and without global mitochondrial depolarization, local removal of mitochondrial content can be achieved by the generation of mitochondrial-derived vesicles MDV that bud-off from the mitochondria and contain matrix components. Mitofusin 1 and mitofusin 2 Mfn are dynamin-like GTPases that control outer membrane fusion, whereas dynamin-like kDa protein, encoded by the OPA1 gene is the dynamin-like GTPase in charge of inner membrane fusion Mishra and Chan, ; Figure 4.

Both Mfn have redundant roles but with certain features: For the complete fusion of mitochondria, the inner mitochondrial membrane must fuse as well. OPA1 is a dynamin-like GTPase protein anchored to the inner mitochondrial membrane that exposes the bulk of the protein to the intermembrane space. Different OPA1 variants, determined by alternative-splicing and proteolytic cleavage, regulate the balance between fusion and fission. Mitochondrial fission facilitates the segregation of damaged mitochondria from a healthy network and mitochondrial transport through neuronal processes.

Dynamin-related protein 1 Drp1 is a cytosolic protein that is recruited to the OMM, where it oligomerizes to form ring-like structures, which upon GTP hydrolysis facilitate membrane constriction Koirala et al.

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Mitochondrial fission occurs at ER-mitochondrial contact sites, where ER tubules mediate constriction before Drp1 recruitment, indicating a role for ER tubules in defining division sites Friedman et al. Less-well understood is the fission of the inner mitochondrial membrane and whether Drp1-mediated outer membrane constriction can also lead to inner membrane scission is still unknown.

However, S-OPA1 fragment accumulation does favor mitochondrial fission.

This discovery opens a new area of study in the field of mitochondrial fission, since further investigation is needed to understand the precise role of S-OPA1, together with its processing-peptidases, in regulating mitochondrial dynamics. The accumulation of dysfunctional mitochondria is suggested to play a key role in the pathology of neurodegenerative diseases. Impaired mitochondria can be selectively targeted and eliminated through a process termed mitophagy. Mitophagy is a highly specialized type of autophagy that consists of three steps: The presence of phospho-ubiquitins stimulates the recruitment and activation of Parkin, which is phosphorylated as well by PINK1 leading to its complete activation Kondapalli et al.

As an E3-ubiquitin ligase, Parkin ubiquitinates many substrates with K and Klinked ubiquitin chains Ordureau et al. In fact, proteins in the OMM can act as mitophagy adapters under certain conditions. Other mitochondrial proteins have been described to act as mitophagy receptors by recruiting the autophagosomal machinery Martinez-Vicente, The need to degrade dysfunctional mitochondria must be balanced with the generation of de novo mitochondria to keep a healthy network Figure 4.

Mitochondrial biogenesis requires a complex coordination of the nuclear and mitochondrial expression programs. NRF1 and NRF2 frequently work together to up-regulate the transcription of several nuclear-encoded genes with essential mitochondrial functions, and to induce the expression of mitochondrial transcription factor A TFAM Virbasius et al. Mitochondrial transport is crucial for the distribution of mitochondria throughout the neuron, from the cell body to the presynaptic terminals, and to accomplish the resupply of newly synthesized mitochondria and mitochondrial proteins Saxton and Hollenbeck, ; Schwarz, ; Misgeld and Schwarz, ; Figure 4.

Mitochondrial transport relies on microtubule-based motors—the anterograde kinesin-1 motor Kif5B and the retrograde dynein motor—attached to the mitochondria by the complex formed by Miro and a mitochondrion-kinesin linker protein, Milton Wang and Schwarz, Stationary mitochondria are held in place by anchoring proteins, such as syntaphilin, through their interaction with microtubules Kang et al. Supporting a pathogenic role for mitochondrial fission, genetic inhibition of pro-fission Drp1 or pro-fusion Mfn1 or OPA1 overexpression are able to prevent cell death induced by these neurotoxins.

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The potential importance of mitochondrial dynamics in PD was revealed in part by the identification of different autosomal recessive and autosomal dominant genes linked to PD. LRRK2 protein has also been linked to mitochondrial dynamics, although its exact role remains to be clarified. In Drosophila, increased mitochondrial length can be rescued by Parkin overexpression Ng et al.

However, others have shown that wild-type LRRK2 interacts with Drp1 and that this interaction was exacerbated by the expression of PD-associated mutants. Moreover, LRRK2 wild-type or GS variant overexpression leads to mitochondrial fragmentation and clearance through the recruitment of Drp1 Niu et al. While PINK1 and Parkin functions in mitophagy have been studied extensively, their contribution to neuronal mitophagy has been challenged recently. Moreover, some groups have failed to observe Parkin recruitment in neurons following mitochondrial depolarization Van Laar et al.

Nonetheless, Cai et al. Besides, Suzuki et al. In the MitoPark mouse model, in which there are clear mitochondrial alterations such as mitochondrial fragmentation and mitochondrial-derived aggregates, no evidence of Parkin recruitment to the defective mitochondria was observed, nor was there any effect of Parkin loss on the progression of neurodegeneration Sterky et al.

What might be the role of PINK1-Parkin-dependent neuronal mitophagy in vivo is therefore still a matter of debate since; i most studies use proliferating cell lines, which poorly reflect the post-mitotic state of degenerating neurons; ii to induce mitophagy, a potent uncoupler CCCP is used, which inducesd a severe mitochondrial depolarization that rarely happens in vivo ; and iii PINK1 and Parkin must be overexpressed in order to detect robust mitophagy.

Interestingly, two in vivo mouse models, the mito-Keima and the mito-QC, have been recently developed Sun et al. These models, which are based on the use of fluorescent reporter proteins, enable the visualization of mitophagy in vivo and might help to finally understand the in vivo role of PINK1-parkin-dependent mitophagy. Of note, loss of function of glucocerebrosidase and SREBF1, both proteins linked to or associated with PD, have been shown to be linked to mitophagy defects Osellame et al.

Importantly, this process takes place faster than mitophagy, suggesting that such a mechanism may help to preserve the integrity of the organelle while damaged components are extracted. Important advances emphasizing the contribution of impaired mitochondrial biogenesis to PD have recently been made. For downregulation of nuclear-encoded complex I genes was found associated with decreased expression of mitobiogenesis factors in PD frontal cortex, pointing at defects in mitochondrial biogenesis as another player in mitochondrial dysfunction Thomas et al.

Parkin also plays a role in the mitochondrial biogenesis pathway through the ubiquitination of Parkin Interacting Substrate PARIS , leading to its ubiquitin-dependent degradation. The aforementioned study is particularly interesting since earlier reports failed to detect neurodegeneration in Parkin germline knock-out models.

Here, there is a conditional knock-out in adult mice, which may suggest that whole body knock-out since birth may result in the development of compensatory mechanisms. The authors argue that similar compensatory mechanisms might occur in PD, accounting for the age-dependence of neurodegeneration observed in PD.

Moreover, upon Parkin loss, mice present reduced mitochondrial size and number, together with structural abnormalities. These mitochondrial alterations depend on PARIS accumulation, since its loss rescues the mitochondrial mass Stevens et al. The tandem PINK1-Parkin also participates in mitochondrial transport regulation by mediating Miro phosphorylation and ubiquitination, which targets the protein for proteasomal degradation Wang et al. Since PINK1 stabilization in the OMM occurs in damaged mitochondria, this mechanism is thought to arrest dysfunctional mitochondria, potentially decreasing their capacity to fuse with healthy ones.

In HD, the balance between fusion and fission is aberrantly shifted toward fission, which is associated with increased levels of Drp1 and Fis1 mRNA and decreased mitofusins in striatal and cortical regions Kim et al. The mechanism leading to exacerbated mitochondrial fission in the presence of mutant huntingtin seems to involve a direct interaction with Drp1. In human post-mortem samples and in transgenic mice lines, mutant huntingtin interacts with Drp1 with a higher affinity than that of the wild-type huntingtin.

This interaction leads to increased Drp1 enzymatic activity and mitochondrial fragmentation. The transfection of a dominant-negative Drp1 mutant Drp1 K38A leads to elongated and uniformly distributed mitochondria and protects against ATP loss and cell death, further supporting a role for Drp1 in mitochondrial fragmentation Wang et al. Since mutant huntingtin increases nitric oxide production, it is hypothesized that mutant huntingtin's interaction with Drp1 enhances its nitrosylation, thereby increasing mitochondrial fragmentation in HD Haun et al.

Huntingtin protein plays an important role in the cargo recognition step in selective autophagy Ochaba et al. Huntingtin acts as a scaffold to bring together different proteins needed for autophagy to take place, such as p62 and ULK1 unc like autophagy activating kinase 1 , which is normally inhibited by its association with mTORC1 mammalian target of ramapycin complex 1. Upon exposure to different stresses, UKL1 is released from mTOR inhibition and interacts with huntingtin in a kinase-active form Rui et al. It is likely, therefore, that the polyglutamine tract affects huntingtin's ability to associate with cargo receptors and autophagy machinery.

While some studies have suggested that the presence of undigested mitochondria could stem from disturbances in autophagosomal transport, which is required for lysosomal fusion to autophagosomes Wong and Holzbaur, , others reported decreased LC3-mitochondria colocalization, arguing in favor of decreased mitophagy due to an impairment in the targeting of defective mitochondria to autophagosomes Khalil et al. Interestingly, PINK1 overexpression could partially rescue the mitophagy defect in mouse striatal cells expressing mutant huntingtin Khalil et al.

Recent work has also linked mutant huntingtin with the impairement of a new form of micro-mitophagy mediated by GAPDH glyceraldehydesphosphate dehydrogenase association with damaged mitochondria upon oxidative stress Hwang et al. All in all, the ability of mutant huntingtin to interfere with different quality control process at the level of the whole mitochondria organelle prevents the correct elimination of damaged mitochondria, which potentially amplifies the deleterious cascade.

Studies on axonal transport in several in vitro models of HD reported impaired mitochondrial trafficking Trushina et al. Wild-type huntingtin is involved in fast axonal trafficking in mammals, and this function has been attributed to its association with huntingtin-associated protein-1 HAP1 Gutekunst et al.

HAP1 is an essential neuronal protein that interacts with dynactin p Engelender et al. In contrast, mutant huntingtin leads to trafficking abnormalities Gunawardena et al. One possibility is that mutant huntingtin leads to abnormal interactions with HAP1, leading to impaired vesicular and organellar trafficking.

Moreover, data from mouse neurons and human HD-affected brain suggests that large mutant huntingtin aggregates impair neuronal trafficking by sequestering wild-type huntingtin and motor proteins from soluble pools Trushina et al. This trafficking defect also affects mitochondrial motility and appears to correlate with glutamine length Trushina et al. Moreover, some polyglutamine-containing N-terminal huntingtin fragments, caused by proteolytic cleavage, can associate with mitochondria and, in vitro , interfere in its association with microtubule-based transport proteins, thus illustrating another mechanism by which mutant huntingtin can impair mitochondrial trafficking Orr et al.

More recently, mitochondrial trafficking was studied in primary hippocampal neurons from bacterial artificial chromosome mouse expressing full length human mutant huntingtin BACHD mice Shirendeb et al. The authors found a decreased number of mitochondria moving anterogradely, together with increased numbers of mitochondria in the cell soma. Neuronal processes were, moreover, devoid of mitochondria, thus further documenting the aberrant mitochondrial transport associated with mutant huntingtin expression.

Mitochondria are essential organelles for the maintenance of neuronal homeostasis. The importance of functional mitochondria to neurons is highlighted by the fact that situations leading to mitochondrial dysfunction are often associated with neurodegenerative diseases. Many of these diseases manifest later in life, where mitochondria seem to be less functional Grimm and Eckert, Mitochondria are at the center of the free radical theory of aging by being both a source and target of ROS. As discussed in this review, the imbalance between ROS production and antioxidant defense in neurodegenerative diseases leads to protein, lipid and DNA oxidation, which in turn affect mitochondrial function.

It was previously considered that when ROS levels exceeded a pathological threshold, this may trigger cell death by apoptosis Figure 5. However, recent developments highlight the increasing potential of mitochondria to defend themselves against various threats Perier et al. Different levels of quality control co-exist within mitochondria to detect and repair defects that affect mitochondrial performance, before the point of inescapable cell death is reached: Thus, impairments in these quality control systems may lead to the accumulation of defective mitochondria, as well as inefficient mitochondrial transport and distribution, leading to synaptic and neuronal degeneration.

However, the more our understanding of protein quality control activities in mitochondria continues to expand, the more questions that are raised. How are all the mitochondrial quality control mechanisms, at the protein and the organelle levels, inter-connected? As mechanisms that flag defective mitochondria are thought to be similar, are these pathways temporarily interlinked and is there crosstalk between them to coordinate mitochondrial homeostasis?

Schematic diagram depicting an hypothesized scenario responsible for mitochondrial dysfunction in PD and HD. ROS are continuously produced in vivo by all body tissues. The presence of mitochondrial translocases, chaperones and proteases within the mitochondrial matrix and intermembrane space acts as a first line of defense against unfolded and oxidized soluble proteins. Once inside the nucleus, these transcription factors promote the upregulation of genes involved in mitochondrial proteostasis.

To maintain a healthy network, mitochondrial are dynamic and can fuse, divide, and move. Once the accumulation of mitochondrial defects exceeds a threshold, patches of mitochondria can be removed through the generation of mitochondrial-derived vesicles MDVs , which transit to the lysosome. Upon complete mitochondrial dysfunction, the entire organelle can be targeted to the autophagosome via so-called mitophagy. When none of the rescue strategies are able to restore mitochondrial function, the cell enters its ultimate destiny, apoptosis.

Clinical trials using general caspase inhibitors such as CEP and TCH failed, maybe because it was too late in the process to intervene. Interestingly, the role of mitochondrial quality control MQC in neuronal health is a recently growing subject for investigation, indicating that MQC might be central to maintain healthy mitochondria. However, until now, no novel therapeutic strategy specifically targeting MQC has been developed.

It is clear that future research focusing on understanding MQC is needed to develop better pharmacological interventions. Despite the many therapeutic advances in PD and HD, no agent has yet been established that has neuroprotective effects in either disease. Some compounds, which target mitochondrial dysfunction and mitochondrial quality control, have shown beneficial effects in mouse models of neurodegenerative diseases and show great promise for treating patients Figure 5. Our current knowledge regarding mitochondrial quality control continues to evolve, opening novel and exciting research paths that will likely help to develop clinically effective therapeutic applications to prevent or combat neurodegenerative diseases.

SF-I and CP wrote the manuscript. All authors contributed to manuscript revision, read and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Discovery of genes activated by the mitochondrial unfolded protein response mtUPR and cognate promoter elements. Sequence and organization of the human mitochondrial genome.

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Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Oxygen toxicity protecting enzymes in the human brain. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum.

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