VPS35 and the mitochondria: Connecting the dots in Parkinson's disease pathophysiology

Cutillo, Gianni; Simon, David K.; Eleuteri, Simona

doi:10.1016/j.nbd.2020.105056

Cited by 22 publications

(15 citation statements)

References 103 publications

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“…In an autosomal dominant PD population study in Japan, VPS35 mutation is also very rare, and the phenotype of motor symptoms in this study is prominent tremor (Ando et al, 2012). VPS35 is a key molecule in the retromer complex within the cell in terms of regulating endosomal trafficking (Cutillo et al, 2020). However new data suggest that VPS35 also regulates mitochondrial dynamics and homeostasis (Cutillo et al, 2020).…”

Section: Park17-vps35mentioning

confidence: 78%

“…VPS35 is a key molecule in the retromer complex within the cell in terms of regulating endosomal trafficking (Cutillo et al, 2020). However new data suggest that VPS35 also regulates mitochondrial dynamics and homeostasis (Cutillo et al, 2020). Also, VPS35 is a critical player in pathways connected to α-synuclein accumulation and clearance (Cutillo et al, 2020).…”

Section: Park17-vps35mentioning

confidence: 99%

“…However new data suggest that VPS35 also regulates mitochondrial dynamics and homeostasis (Cutillo et al, 2020). Also, VPS35 is a critical player in pathways connected to α-synuclein accumulation and clearance (Cutillo et al, 2020).…”

Section: Park17-vps35mentioning

confidence: 99%

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Profiling Non-motor Symptoms in Monogenic Parkinson’s Disease

Liu

2020

Front. Aging Neurosci.

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Parkinson's disease (PD) is the second most common neurodegenerative disease in the elder population, pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra. While the precise mechanisms underlying the pathogenesis of PD remain unknown, various genetic factors have been proved to be associated with PD. To date, at least 23 loci and 19 disease-causing genes for PD have been identified. Although monogenic (often familial) cases account for less than 5% of all PD patients, exploring the phenotypes of monogenic PD can help us understand the disease pathogenesis and progression. Primary motor symptoms are important for PD diagnosis but only detectable at a relatively late stage. Despite typical motor symptoms, various non-motor symptoms (NMS) including sensory complaints, mental disorders, autonomic dysfunction, and sleep disturbances also have negative impacts on the quality of life in PD patients and pose major challenges for disease management. NMS is common in all stages of the PD course. NMS can occur long before the onset of PD motor symptoms or can present in the middle or late stage of the disease accompanied by motor symptoms. Therefore, the profiling and characterization of NMS in monogenic PD may help the diagnosis and differential diagnosis of PD, which thereby can execute early intervention to delay the disease progression. In this review, we summarize the characteristics, clinical phenotypes, especially the NMS of monogenic PD patients carrying mutations of SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and GBA. The clinical implications of this linkage between NMS and PD-related genes are also discussed.

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Section: Park17-vps35mentioning

confidence: 78%

Section: Park17-vps35mentioning

confidence: 99%

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Profiling Non-motor Symptoms in Monogenic Parkinson’s Disease

Liu

2020

Front. Aging Neurosci.

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“…This is critical for neurons [particularly dopaminergic neurons, with ∼4.5 metres of total linear axonal length and ∼2.5 million synapses each (Bolam and Pissadaki, 2012)] as their complex architecture requires mitochondrial relocation from the soma to dendrites, axons and synapses to meet regional metabolic demands (Parrado-Fernandez et al, 2018). The majority of genetic PD proteins locating to mitochondria and mitochondria-ER contact sites are associated with processes influencing or influenced by mitochondrial dynamics and trafficking (Gao et al, 2017;Cutillo et al, 2020). A comprehensive summary of mitochondrial dynamics and trafficking in neuronal function can be found elsewhere (Seager et al, 2020).…”

Section: Restoring Mitochondrial Dynamics and Traffickingmentioning

confidence: 99%

Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities

Prasuhn

Davis

Kumar

2021

Front. Cell Dev. Biol.

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The underlying pathophysiology of Parkinson's disease is complex, but mitochondrial dysfunction has an established and prominent role. This is supported by an already large and rapidly growing body of evidence showing that the role of mitochondrial (dys)function is central and multifaceted. However, there are clear gaps in knowledge, including the dilemma of explaining why inherited mitochondriopathies do not usually present with parkinsonian symptoms. Many aspects of mitochondrial function are potential therapeutic targets, including reactive oxygen species production, mitophagy, mitochondrial biogenesis, mitochondrial dynamics and trafficking, mitochondrial metal ion homeostasis, sirtuins, and endoplasmic reticulum links with mitochondria. Potential therapeutic strategies may also incorporate exercise, microRNAs, mitochondrial transplantation, stem cell therapies, and photobiomodulation. Despite multiple studies adopting numerous treatment strategies, clinical trials to date have generally failed to show benefit. To overcome this hurdle, more accurate biomarkers of mitochondrial dysfunction are required to detect subtle beneficial effects. Furthermore, selecting study participants early in the disease course, studying them for suitable durations, and stratifying them according to genetic and neuroimaging findings may increase the likelihood of successful clinical trials. Moreover, treatments involving combined approaches will likely better address the complexity of mitochondrial dysfunction in Parkinson's disease. Therefore, selecting the right patients, at the right time, and using targeted combination treatments, may offer the best chance for development of an effective novel therapy targeting mitochondrial dysfunction in Parkinson's disease.

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“…Mutation in the VPS35 gene ( PARK17 ), encoding for the Vacuolar protein sorting-associated protein 35 (VPS35), causes autosomal dominant late-onset PD [ 7 ]. VPS35 is a key component of the retromer cargo recognition complex and thus regulates endocytic membrane trafficking, which can influence autophagy in general [ 79 ] ( Figure 1 — trafficking to the lysosome). Relevantly, it has been reported to be a Parkin substrate and in turn, its ubiquitylation regulates retromer-mediated endocytic sorting, including that of the autophagy-essential protein ATG9A [ 80 ].…”

Section: Mitophagy Defects In Pdmentioning

confidence: 99%

Parkinson's disease and mitophagy: an emerging role for LRRK2

Singh

Ganley

2021

Biochemical Society Transactions

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Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

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VPS35 and the mitochondria: Connecting the dots in Parkinson's disease pathophysiology

Cited by 22 publications

References 103 publications

Profiling Non-motor Symptoms in Monogenic Parkinson’s Disease

Profiling Non-motor Symptoms in Monogenic Parkinson’s Disease

Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities

Parkinson's disease and mitophagy: an emerging role for LRRK2

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