Neurodegenerative Mechanisms of ATP13A2-linked Parkinson's Disease and Related Disorders

About This Grant

Project Summary Parkinson’s disease (PD) and Kufor-Rakeb syndrome (KRS) are related progressive neurodegenerative movement disorders caused primarily by the degeneration of dopaminergic neurons in the substantia nigra. Current therapies for PD and KRS are palliative but no disease-modifying therapies exist today. Loss-of-function mutations in the ATP13A2 (PARK9) gene have been identified as a cause of autosomal recessive juvenile-onset KRS and early-onset PD, as well as rare familial forms of hereditary spastic paraplegia, neuronal ceroid lipofuscinosis, and ALS. How the loss of ATP13A2 precipitates dopaminergic neurodegeneration in PD and KRS remains obscure. It is critical to identify the molecular and cellular mechanisms that lead to neurodegeneration due to ATP13A2 mutations in order to better understand the pathophysiology of PD, KRS and related disorders, and for the development of novel therapeutic strategies. ATP13A2 is a lysosomal transmembrane P5B-type ATPase that has recently been shown to play a role in the polyamine transport system. ATP13A2 mediates the lysosomal efflux of the polyamines, spermidine and spermine, into the cytosol and may also regulate the extracellular uptake of polyamines into cells. Impaired polyamine transport can lead to lysosomal dysfunction and impaired mitochondrial homeostasis, at least in cultured cells. How ATP13A2 loss-of-function mutations compromise polyamine transport and lysosomal function in PD-relevant neuronal populations and animal models is not yet known. We have recently developed an adult-onset ATP13A2 conditional knockout (cKO) mouse model of PD/KRS that for the first time exhibits the robust and progressive degeneration of substantia nigra dopaminergic neurons together with lysosomal abnormalities. In the present application, we propose to exploit this new mouse model of PD/KRS to elucidate the pathogenic mechanisms resulting from ATP13A2 loss-of- function mutations, with a key focus on polyamines and lysosomal damage. In Aim 1, we will evaluate lysosomal damage, mitochondrial function, and polyamine levels occurring in the nigrostriatal pathway and in dopaminergic neurons of ATP13A2 cKO mice with advancing age, and the extent, onset and progression of motor, neurotransmitter and neurodegenerative phenotypes. Lysosomal abnormalities will be further defined by proteomic profiling of purified intact lysosomes from dopaminergic neurons, and by single-nuclei RNA sequencing of the substantia nigra to identify lysosomal-related gene signatures. In Aim 2, we will explore the neuroprotective effects of modulating polyamine metabolism in the ATP13A2 cKO mice. We will use complementary pharmacological and genetic approaches to either activate or inhibit the polyamine synthesis pathway via the rate-limiting enzyme ornithine decarboxylase 1, or to specifically target spermidine/spermine metabolism. The impact of altering polyamine metabolism on the onset and progression of PD/KRS-related neurodegeneration and lysosomal damage in the ATP13A2 cKO mice will be evaluated. Our proposal is novel, innovative and timely and will provide critical insight into the mechanisms driving ATP13A2-linked PD and KRS.