Dataset Information

Internalization, axonal transport and release of fibrillar forms of alpha-synuclein.

ABSTRACT: Intra-neuronal protein aggregates made of fibrillar alpha-synuclein (?-syn) are the hallmark of Parkinson's disease (PD). With time, these aggregates spread through the brain following axonal projections. Understanding the mechanism of this spread is central to the study of the progressive nature of PD. Here we review data relevant to the uptake, transport and release of ?-syn fibrils. We summarize several cell surface receptors that regulate the uptake of ?-syn fibrils by neurons. The aggregates are then transported along axons, both in the anterograde and retrograde direction. The kinetics of transport suggests that they are part of the slow component b of axonal transport. Recent findings indicate that aggregated ?-syn is secreted by neurons by non-canonical pathways that may implicate various molecular chaperones including USP19 and the DnaJ/Hsc70 complex. Additionally, ?-syn fibrils may also be released and transmitted from neuron-to-neuron via exosomes and tunneling nanotubes. Understanding these different mechanisms and molecular players underlying ?-syn spread is crucial for the development of therapies that could halt the progression of ?-syn-related degenerative diseases.

SUBMITTER: Bieri G

PROVIDER: S-EPMC5600643 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Internalization, axonal transport and release of fibrillar forms of alpha-synuclein.

Bieri Gregor G Gitler Aaron D AD Brahic Michel M

Neurobiology of disease 20170316 Pt B

Intra-neuronal protein aggregates made of fibrillar alpha-synuclein (α-syn) are the hallmark of Parkinson's disease (PD). With time, these aggregates spread through the brain following axonal projections. Understanding the mechanism of this spread is central to the study of the progressive nature of PD. Here we review data relevant to the uptake, transport and release of α-syn fibrils. We summarize several cell surface receptors that regulate the uptake of α-syn fibrils by neurons. The aggregate ...[more]

PMID: 28323023

Similar Datasets

Project description:Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson's Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.

Dataset Information

Internalization, axonal transport and release of fibrillar forms of alpha-synuclein.

Publications

Internalization, axonal transport and release of fibrillar forms of alpha-synuclein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets