A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers

Farias, Fabiana H.G.; Zeng, Rong; Johnson, Gary S.; Wininger, Fred A.; Taylor, Jeremy F.; Schnabel, Robert D.; McKay, Stephanie; Sanders, Douglas N.; Lohi, Hannes; Seppälä, Eija H.; Wade, Claire M.; Lindblad‐Toh, Kerstin; O’Brien, Dennis P.; Katz, Martin L.

doi:10.1016/j.nbd.2011.02.009

Cited by 115 publications

(95 citation statements)

References 47 publications

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“…y The primarily green autofluorescence of the lipopigment in the present 3 cats was consistent with previous reports of NCL in cats, a ferret, and a Vietnamese potbelly pig, 4,6,21,23 but the storage material in most dogs with NCL tends to exhibit bright yellow autofluorescence at similar excitation wavelengths. 7,13,14,28 Interspecies diversity of the lipopigment constituents and/or differences in the fluorescence microscopy equipment and/or protocol may explain this apparent disparity. The typical distribution of CNS lesions observed in NCL correlates well with the pathological presentations of the present 3 cases.…”

Section: Discussionmentioning

confidence: 99%

“…26 In dogs, the detection of causative NCL candidate genes has been restricted to purebreds, including American Staffordshire Terriers (ARSG), 1 American Bulldogs (CTSD), 2 Tibetan Terriers (ATP13A2), 7 Dachshunds (TPP1 and PPT1), 13,28 an Australian Shepherd (CLN6), 14 English Setters (CLN8), 15 and Border Collies (CLN5). 19 Similarly, purebred sheep such as Borderdales (CLN5), 8 South Hampshires (CLN6), 25 and White Swedish Landraces (CTSD) 29 comprise the majority of reports of ovine NCL.…”

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confidence: 99%

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Characterization of Neuronal Ceroid-Lipofuscinosis in 3 Cats

et al. 2013

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Three young domestic shorthair cats were presented for necropsy with similar histories of slowly progressive visual dysfunction and neurologic deficits. Macroscopic examination of each cat revealed cerebral and cerebellar atrophy, dilated lateral ventricles, and slight brown discoloration of the gray matter. Histologically, there was bilateral loss of neurons within the limbic, motor, somatosensory, visual, and, to a lesser extent, vestibular systems with extensive astrogliosis in the affected regions of all 3 cases. Many remaining neurons and glial cells throughout the entire central nervous system were distended by pale yellow to eosinophilic, autofluorescent cytoplasmic inclusions with ultrastructural appearances typical of neuronal ceroid-lipofuscinoses (NCLs). Differences in clinical presentation and neurological lesions suggest that the 3 cats may have had different variants of NCL. Molecular genetic characterization in the 1 cat from which DNA was available did not reveal any plausible diseasecausing mutations of the CLN1 (PPT1), CLN3, CLN5, CLN8, and CLN10 (CTSD) genes. Further investigations will be required to identify the mutations responsible for NCLs in cats.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Characterization of Neuronal Ceroid-Lipofuscinosis in 3 Cats

et al. 2013

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“…The precise function of ATP13A2 is unclear, but diseaseassociated mutations lead to mistargeting of ATP13A2 to the endoplasmic reticulum instead of the lysosomal membrane, which may impair protein degradation through insufficient acidification of lysosomes. Potentially supporting the idea that ATP13A2 mutations are associated with lysosomal function, Tibetan terriers with recessive ATP13A2 mutations have widespread neurodegeneration and ceroid lipofuscinosis (33). Although Kufor-Rakeb syndrome cases have not been autopsied, if the results in dogs are predictive of the human condition, then ATP13A2 mutations would be associated with a lysosomal storage disease.…”

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confidence: 99%

Mitochondrial Quality Control and Dynamics in Parkinson's Disease

McCoy

Cookson

2012

Antioxidants & Redox Signaling

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Significance: Studies of sporadic cases, toxin models, and genetic causes of Parkinson's disease suggest that mitochondrial dysfunction may be an early feature of pathogenesis. Recent Advances: Compelling evidence of a causal relationship between mitochondrial function and disease was found with the identification of several genes for recessive parkinsonism, PINK1, DJ-1, and parkin. There is evidence that each of these regulates responses to cellular stresses, including oxidative stress and depolarization of the mitochondrial membrane. Specifically, PINK1 and parkin modulate mitochondrial dynamics by promoting autophagic removal of depolarized mitochondria. Mutations in all genes linked to Parkinson's disease lead to enhanced sensitivity to mitochondrial toxins and oxidative stress. Critical Issues: Both increased mitochondrial damage due to complex 1 inhibition, mishandling of calcium, oxidant stress, or impaired clearance of dysfunctional mitochondria would lead to the accumulation of nonfunctional organelles and could contribute to neuronal dysfunction. However, several unanswered questions remain about the underlying mechanism(s) involved. Future Directions: PINK1 and parkin have been demonstrated to regulate mitochondrial dynamics, but the pathways linking PINK1 activity to parkin function are still unclear and warrant further investigation. Antioxid. Redox Signal. 16, 869-882.

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“…A similar link between NCL and Kufor-Rakeb disease was established when ATP13A2 mutations were recently identified in Tibetean terriers with NCL [147,148]. In this context it is interesting that some patients with NCL have parkinsonism and that brains of NCL patients caused by Cathepsin D deficiency (CLN10) show intense alphasynuclein staining [144].…”

Section: Kufor-rakeb Disease (Park9)mentioning

confidence: 64%

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Schneider

Dušek²,

Hardy³

et al. 2013

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Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic.Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.

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A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers

Cited by 115 publications

References 47 publications

Characterization of Neuronal Ceroid-Lipofuscinosis in 3 Cats

Characterization of Neuronal Ceroid-Lipofuscinosis in 3 Cats

Mitochondrial Quality Control and Dynamics in Parkinson's Disease

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

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