Title:Hereditary Parkinsonism-Associated Genetic Variations in PARK9 Locus Lead to Functional Impairment of ATPase Type 13A2
Volume: 18
Issue: 7
Author(s): Jin-Sung Park and Carolyn M. Sue*
Affiliation:
- Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, NSW 2065,Australia
Keywords:
ATP13A2, parkinsonism, Kufor-Rakeb syndrome, neuronal ceroid lipofuscinosis, Zinc, α-synuclein, lysosomes,
mitochondria.
Abstract: Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of Parkinson’s disease (PD)
with juvenile onset of parkinsonism, often accompanied by extra clinical features such as supranuclear
gaze palsy, dementia and generalised brain atrophy. Mutations in ATP13A2, associated with the
PARK9 locus (chromosome 1p36) have been identified in KRS patients. ATP13A2 encodes a lysosomal
P5B-type ATPase which has functional domains similar to other P-type ATPases which mainly
transport cations. Consistently, recent studies suggest that human ATP13A2 may preferably regulate
Zn2+, while ATP13A2 from other species have different substrate selectivity. Until now, fourteen mutations
in ATP13A2 have been associated with KRS, while other mutations have been reported in association
with neuronal ceroid lipofuscinosis (NCL) and early-onset PD. Experimentally, these disease-
associated ATP13A2 mutations have been shown to confer loss-of-function to the protein by
disrupting its protein structure and function to varying degrees, ranging from impairment in ATPase
function to total loss of protein, confirming their pathogenicity. Loss of functional ATP13A2 has
been shown to induce Zn2+ dyshomeostasis. Disturbances in Zn2+ homeostasis impair mitochondrial
and lysosomal function which leads to loss of mitochondrial bioenergetic capacity and accumulation
of lysosomal substrates such as α-synuclein and lipofuscin. Additionally, ATP13A2 appears to be involved
in α-synuclein externalisation through its Zn2+-regulating activity. In this review, we will discuss
all the reported KRS/NCL-associated ATP13A2 mutations along with several PD-associated
mutations which have been experimentally assessed, in respect to their impact on the protein structure
and function of ATP13A2.
