Abstract
Parkinson’s Disease (PD) is a complex neurodegenerative disorder classically characterized by movement impairment. Pathologically, the most striking features of PD are the loss of dopaminergic neurons and the presence of intraneuronal protein inclusions primarily composed of alpha-synuclein (α-syn) that are known as Lewy bodies and Lewy neurites in surviving neurons. Though the mechanisms underlying the progression of PD pathology are unclear, accumulating evidence suggests a prion-like spreading of α-syn pathology. The intracellular homeostasis of α-syn requires the proper degradation of the protein by three mechanisms: chaperone-mediated autophagy, macroautophagy and ubiquitin-proteasome. Impairment of these pathways might drive the system towards an alternative clearance mechanism that could involve its release from the cell. This increased release to the extracellular space could be the basis for α-syn propagation to different brain areas and, ultimately, for the spreading of pathology and disease progression. Here, we review the interplay between α-syn degradation pathways and its intercellular spreading. The understanding of this interplay is indispensable for obtaining a better knowledge of the molecular basis of PD and, consequently, for the design of novel avenues for therapeutic intervention.
Highlights
Parkinson’s DiseaseParkinson’s disease (PD) is the most common neurodegenerative disorder with movement impairment
E46K can inhibit macroautophagy via JNK/Blc2, an mTor independent pathway; (D) On the other hand, two different effects are associated with the A53T -syn mutation: an increase in mitophagy, and accumulation of autophagosomes due to impaired degradation; (E) -syn aggregates cannot be degraded by macroautophagy, leading to the impairment of the pathway
Similar induction of -syn pathology was described in another study comparing the effect of recombinant human -syn and of insoluble brain fractions extracted from Dementia with LB (DLB) patients [173]
Summary
Parkinson’s disease (PD) is the most common neurodegenerative disorder with movement impairment. Hyposmia is one of the prevalent symptoms in early stages of the disease, with several olfactory-related brain areas found severely affected in PD patients [3,4,5,6,7,8]. As the disease progresses, LB pathology appears in other brain areas, including the cerebral cortex, impacting different neural networks and leading to non-motor symptoms such as depression, cognitive decline and hallucination episodes [4,9,10,11]. The first gene linked to familial forms of PD was SNCA, encoding for the protein alpha-synuclein (-syn). Mutations, as well as duplication or triplications of the SNCA gene, are associated with familial forms of PD [18,19,20,21,22,23,24,25]. For all of the above, -syn is regarded as one of the major culprits in both genetic and idiopathic forms of PD
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