Mutated ATP10B increases Parkinson ’s disease risk by compromising lysosomal glucosylceramide export

AbstractParkinson ’s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed w hole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD p atients, 0.97%; 1/226 DLB patients, 0.44%). We established thatATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations inATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk geneG...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Authors: Jones MT, Strassnig MT, Harvey PD Abstract INTRODUCTION: While antipsychotics have been generally successful in treating psychosis in schizophrenia, there is a major treatment gap for negative symptoms and cognitive deficits. Given that these aspects of the disease contribute to poor functional outcomes independently of positive symptoms, treatments would have profound implications for quality of life. The 5-HT2A- receptor has been considered a potential target for interventions aimed at negative and cognitive symptoms and multiple antagonists and inverse agonists of this receptor have been tested. ARE...
Source: Expert Opinion on Emerging Drugs - Category: Drugs & Pharmacology Tags: Expert Opin Emerg Drugs Source Type: research
The increasing ageing global population is causing an upsurge in ailments related to old age, primarily dementia and Alzheimer's disease, frailty, Parkinson's, and cardiovascular disease, but also a general need for general eldercare as well as active and ...
Source: SafetyLit - Category: International Medicine & Public Health Tags: Age: Elder Adults Source Type: news
(University of Copenhagen The Faculty of Health and Medical Sciences) Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain. The model will increase our understanding of how the human brain develops and can thereby help to accelerate the development of stem cell treatments for brain disorders such as Parkinson's disease, epilepsy and dementia.
Source: EurekAlert! - Biology - Category: Biology Source Type: news
There is a considerable overlap between Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). They present a challenge therapeutically, with regard to morbidity and mortality risk. In particular, symptoms of psychosis in these conditions augur a considerably increased burden.To date, there has been a myriad of prospective, retrospective and case studies examining the use of neuroleptics in the treatment of psychotic symptoms in PDD/DLB. Clozapine has the most robust evidence base however its use is limited by agranulocytosis risk and the associated need for frequent blood count monitoring.
Source: Parkinsonism and Related Disorders - Category: Neurology Authors: Tags: Review article Source Type: research
Molecules, Vol. 25, Pages 2444: Anti-aggregation Effects of Phenolic Compounds on α-synuclein Molecules doi: 10.3390/molecules25102444 Authors: Kenjiro Ono Mayumi Tsuji Tritia R. Yamasaki Giulio M. Pasinetti The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson’s disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate...
Source: Molecules - Category: Chemistry Authors: Tags: Review Source Type: research
Though visual illusions and hallucinations are common in dementia with Lewy bodies (DLB) and Parkinson's disease (PD), they are not typically observed clinically in prodromal stages, including isolated REM sleep behavior disorder (iRBD). False-noise errors on the pareidolia test (seeing faces when none are present) may be an effective measure of susceptibility to future hallucinations in iRBD.
Source: Parkinsonism and Related Disorders - Category: Neurology Authors: Tags: Short communication Source Type: research
Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and α-synuclein (α-syn) deposition and Tau tangles are considered hallmarks of Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, α-syn and Tau have been found to co-deposit in the brains of individuals with dementia and parkinsonism, suggesting a potential role of cross-talk between these two proteins in neurodegenerative pathologies. Here we show that monomeric α-syn and the two variants of Tau, Tau23 and K19, synergistically promote amyloid fibrillation, leading t...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Biophysics Source Type: research
HS1-associated protein X-1 (HAX-1) and presenilin-associated rhomboid-like protein (PALR) were reported to play an important role in the activation of HtrA2/Omi, which is also designated PARK13, in the mitochondria. To elucidate the role of HAX-1 and PARL in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB), we performed immunohistochemical studies on HtrA2/Omi, HAX-1 and PARL using autopsied brains from 8 normal subjects, 10 patients with PD and 5 patients with DLB. In accordance with our previous report, brainstem-type and cortical Lewy bodies were strongly immunopositive for HtrA2/Omi.
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Source Type: research
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Source: Zeitschrift fur Gerontologie und Geriatrie - Category: Geriatrics Authors: Tags: Z Gerontol Geriatr Source Type: research
patsiaris The increasing ageing global population is causing an upsurge in ailments related to old age, primarily dementia and Alzheimer’s disease, frailty, Parkinson’s, and cardiovascular disease, but also a general need for general eldercare as well as active and healthy ageing. In turn, there is a need for constant monitoring and assistance, intervention, and support, causing a considerable financial and human burden on individuals and their caregivers. Interconnected sensing technology, such as IoT wearables and devices, present a promising solution for objective, reliable, and remote monitoring...
Source: Sensors - Category: Biotechnology Authors: Tags: Review Source Type: research
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