Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease

Pitcairn, Caleb; Wani, Willayat Yousuf; Mazzulli, Joseph R.

doi:10.1016/j.nbd.2018.03.008

Cited by 54 publications

(40 citation statements)

References 135 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because of the extremely long transport routes, proper cell homeostasis, which is mediated by a perfectly functioning endolysosomal system, is of utmost importance for motoneurons. Lysosomal dysfunction appears to be a major pathomechanism for several autosomal-recessive HSPs and additional neurodegenerative diseases ( Kenney and Benarroch, 2015 ; Lo Giudice et al, 2014 ; Noreau et al, 2014 ; Pitcairn et al, 2018 ). We hypothesise that imbalances in the endolysosomal system ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Expression of N471D strumpellin leads to defects in the endolysosomal system

Lin

Rijal

Karow

et al. 2018

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Hereditary spastic paraplegias (HSPs) are genetically diverse and clinically characterised by lower limb weakness and spasticity. The N471D and several other point mutations of human strumpellin (Str; also known as WASHC5), a member of the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complex, have been shown to cause a form of HSP known as spastic paraplegia 8 (SPG8). To investigate the molecular functions of wild-type (WT) and N417D Str, we generated Dictyostelium Str− cells and ectopically expressed StrWT-GFP or StrN471D-GFP in Str− and WT cells. Overexpression of both proteins apparently caused a defect in cell division, as we observed a clear increase in multinucleate cells. Real-time PCR analyses revealed no transcriptional changes in WASH complex subunits in Str− cells, but western blots showed a twofold decrease in the SWIP subunit. GFP-trap experiments in conjunction with mass-spectrometric analysis revealed many previously known, as well as new, Str-interacting proteins, and also proteins that no longer bind to StrN471D. At the cellular level, Str− cells displayed defects in cell growth, phagocytosis, macropinocytosis, exocytosis and lysosomal function. Expression of StrWT-GFP in Str− cells rescued all observed defects. In contrast, expression of StrN471D-GFP could not rescue lysosome morphology and exocytosis of indigestible material. Our results underscore a key role for the WASH complex and its core subunit, Str, in the endolysosomal system, and highlight the fundamental importance of the Str N471 residue for maintaining lysosome morphology and dynamics. Our data indicate that the SPG8-causing N471D mutation leads to a partial loss of Str function in the endolysosomal system.

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of N471D strumpellin leads to defects in the endolysosomal system

Lin

Rijal

Karow

et al. 2018

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…Different mutations in the genes involved in familial PD are associated with pathways of mitochondrial dysfunction, while some of these compromised pathways have been established as important factors in the pathophysiology of sporadic PD [ 261 ]. Autophagic/lysosomal dysfunction are also thought to have a key role in the pathogenesis of the disease, with many PD mutations being associated with defects in these pathways [ 262 , 263 ]. Interestingly, a number of key mutations are involved both in mitochondrial and autophagic/lysosomal dysfunction pathways, revealing a compelling crosstalk that lies in the center of the pathophysiology of PD [ 264 ].…”

Section: Cellular Senescence In Alzheimer’s Disease Parkinson’s Dmentioning

confidence: 99%

Ageing, Cellular Senescence and Neurodegenerative Disease

Kritsilis

Rizou

Koutsoudaki

et al. 2018

IJMS

290

190

View full text Add to dashboard Cite

Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence is a homeostatic biological process that has a key role in driving ageing. There is evidence that senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and may predispose a person to the appearance of a neurodegenerative condition or may aggravate its course. Research into senescence has long been hindered by its variable and cell-type specific features and the lack of a universal marker to unequivocally detect senescent cells. Recent advances in senescence markers and genetically modified animal models have boosted our knowledge on the role of cellular senescence in ageing and age-related disease. The aim now is to fully elucidate its role in neurodegeneration in order to efficiently and safely exploit cellular senescence as a therapeutic target. Here, we review evidence of cellular senescence in neurons and glial cells and we discuss its putative role in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis and we provide, for the first time, evidence of senescence in neurons and glia in multiple sclerosis, using the novel GL13 lipofuscin stain as a marker of cellular senescence.

show abstract

“…Insights from fly and mouse PD models will be covered, and specific cell-type mechanisms for α-Syn secretion and uptake will be discussed and compared. α-Syn trafficking, rather than its clearance and degradation, is emphasized as the latter has been a subject for a number of excellent reviews recently ( Kinghorn et al., 2017 ; Pitcairn et al., 2018 ). Of note, impaired trafficking and defects in other trafficking components, in addition to α-Syn, also play significant roles in PD pathology.…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein Trafficking in Parkinson’s Disease: Insights From Fly and Mouse Models

Cheng

Lü

et al. 2018

ASN Neuro

View full text Add to dashboard Cite

Protein aggregation and accumulation are common pathological hallmarks in neurodegenerative diseases. To efficiently clear and eliminate such aggregation becomes an important cellular strategy for cell survival. Lewy bodies inclusion and aggregation of α-Synuclein (α-Syn) during the pathogenesis of Parkinson’s disease (PD) serve as a good example and are potentially linked to other pathological PD features such as progressive dopaminergic neuron cell death, behavioral defects, and nonmotor symptoms like anosmia, cognitive impairment, and depression. Years of research have revealed a variety of mechanisms underlying α-Syn aggregation, clearance, and spread. Particularly, vesicular routes associated with the trafficking of α-Syn, leading to its aggregation and accumulation, have been shown to play vital roles in PD pathogenesis. How α-Syn proteins propagate among cells in a prion-like manner, either from or to neurons and glia, via means of uptake or secretion, are questions under active investigation and have been of central interest in the field of PD study. This review covers components and pathways of possible vesicular routes involved in α-Syn trafficking. Events including but not limited to exocytosis and endocytosis will be discussed within the context of an overall cellular trafficking theme. Recent advances on α-Syn trafficking mechanisms and their significance in mediating PD pathogenesis will be thoroughly reviewed, ending with a discussion on the advantages and limitations of different animal PD models.

show abstract

Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease

Cited by 54 publications

References 135 publications

Expression of N471D strumpellin leads to defects in the endolysosomal system

Expression of N471D strumpellin leads to defects in the endolysosomal system

Ageing, Cellular Senescence and Neurodegenerative Disease

α-Synuclein Trafficking in Parkinson’s Disease: Insights From Fly and Mouse Models

Contact Info

Product

Resources

About