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Proteolysis of ?-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology.

ABSTRACT: Progression of ?-synuclein inclusion pathology may occur through cycles of release and uptake of ?-synuclein aggregates, which induce additional intracellular ?-synuclein inclusion pathology. This process may explain (i) the presence of ?-synuclein inclusion pathology in grafted cells in human brains, and (ii) the slowly progressive nature of most human ?-synucleinopathies. It also provides a rationale for therapeutic targeting of extracellular aggregates to limit pathology spread. We investigated the cellular mechanisms underlying intraneuronal ?-synuclein aggregation following exposure to exogenous preformed ?-synuclein amyloid fibrils. Exogenous ?-synuclein fibrils efficiently attached to cell membranes and were subsequently internalized and degraded within the endosomal/lysosomal system. However, internalized ?-synuclein amyloid fibrils can apparently overwhelm the endosomal/lysosomal machinery leading to the induction of intraneuronal ?-synuclein inclusions comprised of endogenous ?-synuclein. Furthermore, the efficiency of inclusion formation was relatively low in these studies compared to studies using primary neuronal-glial cultures over-expressing ?-synuclein. Our study indicates that under physiologic conditions, endosomal/lysosomal function acts as an endogenous barrier to the induction of ?-synuclein inclusion pathology, but when compromised, it may lower the threshold for pathology induction/transmission. Cover Image for this issue: doi: 10.1111/jnc.13787.

SUBMITTER: Sacino AN

PROVIDER: S-EPMC5452425 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Proteolysis of α-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology.

Sacino Amanda N AN Brooks Mieu M MM Chakrabarty Paramita P Saha Kaustuv K Khoshbouei Habibeh H Golde Todd E TE Giasson Benoit I BI

Journal of neurochemistry 20160819 4

Progression of α-synuclein inclusion pathology may occur through cycles of release and uptake of α-synuclein aggregates, which induce additional intracellular α-synuclein inclusion pathology. This process may explain (i) the presence of α-synuclein inclusion pathology in grafted cells in human brains, and (ii) the slowly progressive nature of most human α-synucleinopathies. It also provides a rationale for therapeutic targeting of extracellular aggregates to limit pathology spread. We investigat ...[more]

PMID: 27424880

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Project description:Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

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Proteolysis of ?-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology.

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Proteolysis of α-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology.

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