Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson’s disease pathogenesis

Abstract

Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) are symptomatically characterized by parkinsonism, with the latter presenting additionally a distinctive range of atypical features. Although the majority of patients with PD and APS appear to be sporadic, genetic causes of several rare monogenic disease variants were identified. The knowledge acquired from these genetic factors indicated that defects in vesicular transport pathways, endo-lysosomal dysfunction, impaired autophagy-lysosomal protein and organelle degradation pathways, α-synuclein aggregation and mitochondrial dysfunction play key roles in PD pathogenesis. Moreover, membrane dynamics are increasingly recognized as a key player in the disease pathogenesis due lipid homeostasis alterations, associated with lysosomal dysfunction, caused by mutations in several PD and APS genes. The importance of lysosomal dysfunction and lipid homeostasis is strengthened by both genetic discoveries and clinical epidemiology of the association between parkinsonism and lysosomal storage disorders (LSDs), caused by the disruption of lysosomal biogenesis or function. A synergistic coordination between vesicular trafficking, lysosomal and mitochondria defects exist whereby mutations in PD and APS genes encoding proteins primarily involved one PD pathway are frequently associated with defects in other PD pathways as a secondary effect. Moreover, accumulating clinical and genetic observations suggest more complex inheritance patters of familial PD exist, including oligogenic and polygenic inheritance of genes in the same or interconnected PD pathways, further strengthening their synergistic connection. Here, we provide a comprehensive overview of PD and APS genes with functions in vesicular transport, lysosomal and mitochondrial pathways, and highlight functional and genetic evidence of the synergistic connection between these PD associated pathways.

The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

“…The implication of mitochondrial dysfunction was the earliest mechanistic insight into PD pathogenesis, however, an increasing amount of evidence is indicative of an important role of the endo-lysosomal pathway in PD [ 120 , 121 , 122 ]. The endo-lysosomal pathway is important for protein homeostasis and consists of endocytosis, retromer and autolysosome [ 123 , 124 , 125 ] that we will separately discuss.…”

Single-cell sequencing of the human midbrain reveals glial activation and a neuronal state specific to Parkinson’s disease

“…Parkinson’s disease (PD) is a neurological disorder that is characterized by a progressive loss of neuromelanin-containing dopaminergic neurons (DaNs) in the substantia nigra (SN) 1,2 . Age, genetic, and environmental factors contribute to PD pathogenesis, but disease pathology and etiology remain mostly unknown 3 .…”

Synaptic Function and Dysfunction in Lysosomal Storage Diseases

“…For example, mutations in the gene GBA (encoding for glucosylceramidase, deficient in Gaucher’s disease, GD) are genetic risk factors associated with PD (Barkhuizen et al, 2016 ; Gan-Or et al, 2018 ; Sidransky et al, 2009 ). Additionally, SMPD1 (acid sphingomyelinase, deficient in Niemann Pick type A, B), ASAH1 (acid ceramidase, deficient in Farber’s disease and spinal muscular atrophy with progressive myoclonic epilepsy), ARSA [arylsulfatase A, deficient in metachromatic leukodystrophy (MLD)] and GALC [lysosomal galactosylceramidase, deficient in Krabbe’s disease (KD)] are also associated with vulnerability to develop adult onset neurodegenerative disorders, particularly PD (Smolders and Van Broeckhoven, 2020 ). These studies underline the possibility that mechanisms involved in synaptic failure in LSDs may also be playing an active role in other neurodegenerative diseases.…”