Objective: This project aimed to investigate whether the CMA lysosomal pathway induction may benefit the highest-order mammalian synucleinopathy model, the non-human primate, by targeting CMA’s rate-limiting step, the LAMP2A receptor.

Background: Lysosomal impairment is strongly implicated in Parkinson’s disease (PD). Chaperone-Mediated Autophagy (CMA) is a major lysosomal pathway responsible for alpha-synuclein (aSyn) clearance but, at the same time, can be a direct target of aSyn-related neurotoxic effects. The rate of CMA depends mainly on the levels of LAMP2A (lysosomal transmembrane protein 2A) and the presence within the lysosomal lumen of the lys-HSC70 chaperone.

Method: To this end, we performed bilateral injections of the AAV2/9-LAMP2A-HA vector (or the control vector) in the SNpc of 14 male rhesus macaque monkeys (Macaca mulatta) together with unilateral intrastriatal injections of low doses of aSyn-containing Lewy body (LB) extracts purified from the SNpc of PD brains (or extracts from non-PD brains as control).

Animals were terminated 15 months later, and brains were harvested. Extensive histochemical and biochemical analyses were performed to evaluate cerebral pathological markers known to be affected in PD. We characterized the pattern of dopaminergic loss in the striatum and the SNpc, the regional distribution of aSyn immunoreactivity in several brain structures, its pathological status (i.e., S129 phosphorylation), and the occurrence of lysosomal dysfunction.

Results: Our data so far show that viral-mediated LAMP2A overexpression protects dopaminergic neurons from the cell loss induced by the injection of PD brain extracts. Interestingly, LAMP2A-injected animals displayed significantly improved performance in the cognitive behavioral tests suggesting that our gene therapy approach induces a beneficial cognitive effect. Lastly, LAMP2A overexpression decreases extracellular aSyn levels in the monkey biological fluids.

Conclusion: In conclusion, this study demonstrates that viral-based overexpression of LAMP2A attenuates the dopaminergic neurodegeneration in a non-human primate model of PD. These results support the idea that enhancement of CMA through LAMP2A overexpression or other means, possibly pharmacological, might open new therapeutic opportunities for slowing down the degenerative process in patients with PD and related synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/harnessing-chaperone-mediated-autophagy-through-viral-based-lamp2a-overexpression-in-non-human-primates-as-a-treatment-of-parkinsons-disease/