Systemic Metabolic Alteration Dependent on the Thyroid-Liver Axis in Early PD.

Objective: Parkinson's disease (PD) is a common neurodegenerative disease characterized by initial involvement of the olfactory bulb/amygdala or autonomic nerves followed by nigral degeneration. Although autonomic innervation strictly regulates multiorgan systems, including endocrine functions, circulation, and digestion, how dysautonomia in PD affects systemic metabolism has not been identified. In this study, we tried to estimate the pathogenic linkage of PD by nuclear medicine techniques, trans-omic analysis of blood samples, and cultured cell experiments.

Shared Metabolic Profile of Caffeine in Parkinsonian Disorders.

Objective: The objective of this study was to determine comprehensive metabolic changes of caffeine in the serum of patients with parkinsonian disorders including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) and to compare this with healthy control serum.

Methods: Serum levels of caffeine and its 11 downstream metabolites from independent double cohorts consisting of PD (n = 111, 160), PSP (n = 30, 19), MSA (n = 23, 17), and healthy controls (n = 43, 31) were examined by liquid chromatography-mass spectrometry. The association of each metabolite with clinical parameters and medication was investigated.

A metabolic profile of polyamines in parkinson disease: A promising biomarker.

Objective: Aging is the highest risk factor for Parkinson disease (PD). Under physiological conditions, spermidine and spermine experimentally enhance longevity via autophagy induction. Accordingly, we evaluated the ability of each polyamine metabolite to act as an age-related, diagnostic, and severity-associated PD biomarker.

Iron Supply via NCOA4-Mediated Ferritin Degradation Maintains Mitochondrial Functions.

Iron is an essential nutrient for mitochondrial metabolic processes, including mitochondrial respiration. Ferritin complexes store excess iron and protect cells from iron toxicity. Therefore, iron stored in the ferritin complex might be utilized under iron-depleted conditions.

p150 deficiency impairs effective fusion between autophagosomes and lysosomes due to their redistribution to the cell periphery.

Dynein-dynactin has an indispensable role in autophagy and p150 is the largest component of the dynactin complex. Here, we characterized the effects of knockdown (KD) of endogenous p150 and of the pathogenic mutation of p150 found in autosomal dominant p150-associated disorders [hereditary motor neuronopathy with vocal paresis (HMN7B) and Perry syndrome] on autophagy. Overexpression of the p150 pathogenic mutant or siRNA KD of p150 promoted the localization of lysosomes at the cell periphery and increased the number of autophagosomes, suggesting partial blockage of autophagic flux.

Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease.

Objective: To investigate the kinetics and metabolism of caffeine in serum from patients with Parkinson disease (PD) and controls using liquid chromatography-mass spectrometry.

Methods: Levels of caffeine and its 11 metabolites in serum from 108 patients with PD and 31 age-matched healthy controls were examined by liquid chromatography-mass spectrometry. Mutations in caffeine-associated genes were screened by direct sequencing.

Decreased long-chain acylcarnitines from insufficient β-oxidation as potential early diagnostic markers for Parkinson's disease.

Increasing evidence shows that metabolic abnormalities in body fluids are distinguishing features of the pathophysiology of Parkinson's disease. However, a non-invasive approach has not been established in the earliest or pre-symptomatic phases. Here, we report comprehensive double-cohort analyses of the metabolome using capillary electrophoresis/liquid chromatography mass-spectrometry.

Homozygous alpha-synuclein p.A53V in familial Parkinson's disease.

We have assessed the frequency of alpha-synuclein (SNCA) mutations in Japanese patients with familial or sporadic Parkinson's disease (PD) and surveyed their associated clinical manifestations. We screened SNCA exon 3 in 988 patients without SNCA multiplications (430 with autosomal dominant PD and 558 with sporadic PD). We detected 1 patient harboring a homozygous SNCA p.

Immunocytochemical Monitoring of PINK1/Parkin-Mediated Mitophagy in Cultured Cells.

Both PINK1 and parkin are the responsible genes (PARK6 and PARK2, respectively) for familial early-onset Parkinson's disease (PD). Several lines of evidences have suggested that mitochondrial dysfunction would be associated with PD pathogenesis. Lewy body, one of PD pathological hallmarks, contains alpha-synuclein, a familial PD (PARK1/4)-gene product, which is eliminated by macroautophagy, while PINK1 and parkin coordinately mediate mitophagy (hereafter called as PINK1/parkin-mediated mitophagy) reported firstly by Youle's group.

Ethambutol neutralizes lysosomes and causes lysosomal zinc accumulation.

Ethambutol is a common medicine used for the treatment of tuberculosis, which can have serious side effects, such as retinal and liver dysfunction. Although ethambutol has been reported to impair autophagic flux in rat retinal cells, the precise molecular mechanism remains unclear. Using various mammalian cell lines, we showed that ethambutol accumulated in autophagosomes and vacuolated lysosomes, with marked Zn(2+) accumulation.

P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway.

Mutations in p150glued cause hereditary motor neuropathy with vocal cord paralysis (HMN7B) and Perry syndrome (PS). Here we show that both overexpression of p150glued mutants and knockdown of endogenous p150glued induce apoptosis. Overexpression of a p150glued plasmid containing either a HMN7B or PS mutation resulted in cytoplasmic p150glued-positive aggregates and was associated with cell death.

Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition.

Caffeine is one of the most frequently ingested neuroactive compounds. All known mechanisms of apoptosis induced by caffeine act through cell cycle modulation or p53 induction. It is currently unknown whether caffeine-induced apoptosis is associated with other cell death mechanisms, such as autophagy.

Mutation analyses in amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula, Japan.

To clarify the genetic background of amyotrophic lateral sclerosis (ALS)/parkinsonism-dementia complex (PDC) of the Kii peninsula, Japan (Kii ALS/PDC), we performed extended mutation analyses of three patients with pathologically diagnosed Kii ALS/PDC. Direct sequencing analyses were performed in 19 genes, including ALS/frontotemporal lobar degeneration (FTLD)-related genes (SOD2, SOD3, ALS2/alsin, SMN1, PGRN, ANG, VEGF, VCP, VAPB, DCTN1, CHMP2B, and TARDBP or TDP-43), tauopathy-related gene (GSK3beta), and parkinsonism-related genes (alpha-synuclein, LRRK2, parkin, DJ-1, PINK1, and ATP13A2). Gene dosage analyses were conducted in screening of MAPT, alpha-synuclein, TDP-43 (or TARDBP), GSK3beta, and parkin.

Familial Parkinsonism with digenic parkin and PINK1 mutations.

To clarify the genetic correlation between parkin and PINK1, we screened for PINK1 mutations in 175 parkinsonism patients with parkin mutations. We detected two sibling pairs and one sporadic patient carrying both parkin and PINK1 mutations. The age at onset of Parkinsonism of patients with the digenic mutations was lower than that of patients with the same parkin mutation alone.

Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease.

Objectives: To determine the frequency, distribution, and clinical features of Parkinson disease (PD) with PINK1 mutations.

Design: Retrospective clinical and genetic review.

Setting: University hospital.

Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia.

A family history of Parkinson's disease (PD) is the most commonly reported risk factor after age, suggesting a genetic component to the disease in a sub-group of patients. Mutations in at least six genes have been identified that can lead to monogenic forms of PD. We screened a sample of 74 early-onset PD cases out of a cohort of 950 patients (onset <50 years) for genetic abnormalities in known familial Parkinsonism genes.

Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population.

To assess the effect of genetic factors on sporadic Parkinson disease, we performed a case-control study of a variant (G2385R) in Leucine-Rich Repeat kinase 2 among the Japanese population. The G2385R (c.7153G>A) variant was reported as a risk factor for sporadic Parkinson disease in the Chinese population from Taiwan and Singapore.

Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries.

We screened LRRK2 mutations in exon 41 in 904 parkin-negative Parkinson's disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.

Pseudo-autosomal dominant inheritance of PARK2: two families with parkin gene mutations.

We report two families (Family S and Family N) with early-onset parkinsonism in two generations. The mode of inheritance appeared to be autosomal dominant, however, haplotye analysis suggested linkage to chromosome 6q25.2-27, the PARK2 locus, and all affected members were homozygotes in their haplotypes.