TY  - JOUR
AU  - Estrada-Cuzcano, Alejandro
AU  - Martin, Shaun
AU  - Chamova, Teodora
AU  - Synofzik, Matthis
AU  - Timmann, Dagmar
AU  - Holemans, Tine
AU  - Andreeva, Albena
AU  - Reichbauer, Jennifer
AU  - De Rycke, Riet
AU  - Chang, Dae-In
AU  - van Veen, Sarah
AU  - Samuel, Jean
AU  - Schöls, Ludger
AU  - Pöppel, Thorsten
AU  - Mollerup Sørensen, Danny
AU  - Asselbergh, Bob
AU  - Klein, Christine
AU  - Zuchner, Stephan
AU  - Jordanova, Albena
AU  - Vangheluwe, Peter
AU  - Tournev, Ivailo
AU  - Schüle, Rebecca
TI  - Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).
JO  - Brain
VL  - 140
IS  - 2
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-05464
SP  - 287-305
PY  - 2017
AB  - Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.
KW  - Adult
KW  - Animals
KW  - Cells, Cultured: cytology
KW  - Cells, Cultured: ultrastructure
KW  - Chlorocebus aethiops
KW  - Cognition Disorders: etiology
KW  - Cognition Disorders: genetics
KW  - Enzyme Inhibitors: pharmacology
KW  - Family Health
KW  - Gene Expression Regulation: drug effects
KW  - Gene Expression Regulation: genetics
KW  - Genetic Predisposition to Disease: genetics
KW  - Humans
KW  - Leupeptins: pharmacology
KW  - Lysosomes: drug effects
KW  - Lysosomes: metabolism
KW  - Lysosomes: ultrastructure
KW  - Male
KW  - Mental Disorders: etiology
KW  - Mental Disorders: genetics
KW  - Middle Aged
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Mitochondria: ultrastructure
KW  - Mutation: genetics
KW  - Neuropsychological Tests
KW  - Proton-Translocating ATPases: genetics
KW  - Psychiatric Status Rating Scales
KW  - Spastic Paraplegia, Hereditary: complications
KW  - Spastic Paraplegia, Hereditary: diagnostic imaging
KW  - Spastic Paraplegia, Hereditary: genetics
KW  - ATP13A2 protein, human (NLM Chemicals)
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - Leupeptins (NLM Chemicals)
KW  - Proton-Translocating ATPases (NLM Chemicals)
KW  - benzyloxycarbonylleucyl-leucyl-leucine aldehyde (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28137957
C2  - pmc:PMC5278306
DO  - DOI:10.1093/brain/aww307
UR  - https://pub.dzne.de/record/139142
ER  -