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Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
Several other genetic parkinsonian syndromes have been attributed PARK loci, but are not characterized by classical parkinsonism, and exhibit several atypical and more complex phenotypes. Mutations in the recessive ATP13A2/PARK9 gene have been detected in a number of families with the Kufor–Rakeb syndrome which consists of juvenile parkinsonism, early response to L-dopa, but with associated spasticity, dementia, supranuclear gaze palsy and facial myoclonus. Mutations in PLA2G6/PARK14 are a cause of adult onset dystonia and parkinsonism with a good response to L-dopa but early dyskinesias. Interestingly, mutations in PLA2G6 also cause an infantile neuraxonal dystrophy.
Organoid and pluripotent stem cells in Parkinson’s disease modeling: an expert view on their value to drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Nick Marotta, Soojin Kim, Dimitri Krainc
PARK9 encodes a lysosomal type 5 P-type ATPase involved in cation homeostasis, ATP13A2. The loss of ATP13A2 function leads to lysosomal dysfunction and the accumulation of α-synuclein seen in Kufor-Rakeb syndrome (KRS), a rare form of juvenile-onset PD and familial PD [139,140]. Recently, loss of function mutations of ATP13A2 in iPSC-DA neurons have exhibited α-synuclein accumulation as well as impaired lysosomal exocytosis due to the disruption of calcium homeostasis [141,142]. Interestingly, ATP13A2 overexpression or activators of the lysosomal calcium channel TRPML1 (transient receptor potential mucolipin 1) were able to increase α-synuclein secretion and lysosomal exocytosis, and prevent neuronal toxicity [142]. ATP13A2 thus offers potential as a therapeutic target for PD-related synucleinopathies by increasing lysosomal exocytosis and neuronal secretion of intracellular α-synuclein.
Current and future clinical utilities of Parkinson’s disease and dementia biomarkers: can they help us conquer the disease?
Published in Expert Review of Neurotherapeutics, 2019
Gilbert Ho, Yoshiki Takamatsu, Masaaki Waragai, Ryoko Wada, Shuei Sugama, Takato Takenouchi, Masayo Fujita, Alysha Ali, Mindy Hsin-I Hsieh, Makoto Hashimoto
Additionally, PTEN-induced kinase 1 (PINK1/PARK6), the mutations of which result in recessive early-onset parkinsonism, has been revealed to play an important role in IGF-1/insulin signaling. Compared to wild type mice, IGF-1/insulin signaling is shown to be down-regulated in cultured PINK1 knockout mouse cortical neurons, resulting in reduced Akt and downstream GSK-3β phosphorylation, suggesting that insulin signaling defects might be instrumental in PINK1-related parkinsonism [67]. In turn, reduced Akt activity also leads to reduced PINK1 and Parkin recruitment to damaged mitochondria and reduced mitophagy [68]. Interestingly, significantly reduced periaqueductal gray expression of Atp13a2, a transmembranous lysosomal P5-type ATPase of unclear function, was also demonstrated in PINK1 knockout rats, indicating that defective lysosomal degradation mechanisms may underlie PINK1 and αS pathology in PD [69]. Most notable, mutations in Atp13a2 (PARK9) result in Kufor-Rakeb Syndrome (KRS), an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia [70], and as a clue to its normal function, Atp13a2 (PARK9) promotes both exosome and αS secretion from cultured H4 cells, which may have substantial implications for the regulation of biomarkers in neurodegeneration [71]. PINK1 and Atp13a2, therefore, might be investigated further as possible biomarkers in PD and dementia.
Ocular Manifestations of Neuronal Ceroid Lipofuscinoses
Published in Seminars in Ophthalmology, 2021
Rohan Bir Singh, Prakash Gupta, Akash Kartik, Naba Farooqui, Sachi Singhal, Sukhman Shergill, Kanwar Partap Singh, Aniruddha Agarwal
CLN-12 disease occurs due to mutations in ATP13A2, belonging to the family of ATPases that inorganic transport cations and other substrates across cell membranes.142,143 This gene is also implicated in Kufor Rakeb syndrome, a rare parkinsonian phenotype with juvenile-onset.144 The patients typically present with learning difficulties, extrapyramidal signs, cerebellar ataxia, bulbar syndrome, and progressive loss of muscle strength. The diagnostic neuroimaging in patients shows cortical and subcortical atrophy, and ophthalmologically, no retinal involvement is noted, but patients present with slow vertical ocular movements.144