gut-transit-defects-drosophila-models-monogenic-parkinson-s-disease

Gut Transit Defects in <em>Drosophila</em> Models of Monogenic Parkinson's Disease Using a Constipation Assay

Parkinson's disease (PD) is a common neurodegenerative motor disorder and is frequently accompanied by several non-motor symptoms. Among the latter, ...

University of Luebeck and University Hospital Schleswig-Holstein

During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry.

Neurological symptoms and complications in predominantly hospitalized COVID-19 patients: Results of the European multinational Lean European Open Survey on SARS-Infected Patients (LEOSS).

Mitophagy and energy production are two functionalities in which PINK1 plays a key role. Loss of PINK1 is one of the genetic causes of Parkinson disease (PD), suggesting both processes are important in PD pathogenesis. Nonetheless, it remains unclear whether these processes are connected or independent of one another. Sphingolipids, including ceramide, have recently emerged as an important new player in the development of PD, however, how alterations in ceramide levels are mechanistically linked to PD remained elusive. In a recently published study, we demonstrated that ceramide accumulates in mitochondria and initiates ceramide-induced mitophagy, thereby compensating for the lack of PINK1-dependent mitophagy upon PINK1 deficiency. However, ceramide accumulation negatively affects ß-oxidation, further aggravating the electron transport chain (ETC) defect caused by PINK1 deficiency and resulting in an additional requirement for mitophagy. Thus, we showed that ceramide serves as a link between the ETC and mitophagy upon PINK1 deficiency. Interruption of this vicious cycle via stimulation of ß-oxidation or reduction of ceramide levels can provide a novel therapeutic target in the treatment of PINK1-related PD.

Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.

Let's make science, not war!

Genetic Testing for  and  Mutations: Is it Time for Routine Use?

Genetic testing has become a valuable diagnostic tool for movement disorders due to substantial advancements in understanding their genetic basis. However, the heterogeneity of movement disorders poses a significant challenge, with many genes implicated in different subtypes. This paper aims to provide a neurologist's perspective on approaching patients with hereditary hyperkinetic disorders with a focus on select forms of dystonia, paroxysmal dyskinesia, chorea, and ataxia. Age at onset, initial symptoms, and their severity, as well as the presence of any concurrent neurological and non-neurological features, contribute to the individual clinical profiles of hereditary non-parkinsonian movement disorders, aiding in the selection of appropriate genetic testing strategies. There are also more specific diagnostic clues that may facilitate the decision-making process and may be highly specific for certain conditions, such as diurnal fluctuations and l-dopa response in dopa-responsive dystonia, and triggering factors, duration and frequency of attacks in paroxysmal dyskinesia. While the genetic and mutational spectrum across non-parkinsonian movement disorders is broad, certain groups of diseases tend to be associated with specific types of pathogenic variants, such as repeat expansions in many of the ataxias. Some of these pathogenic variants cannot be detected by standard methods, such as panel or exome sequencing, but require the investigation of intronic regions for repeat expansions, such as Friedreich's or FGF14-linked ataxia. With our advancing knowledge of the genetic underpinnings of movement disorders, the incorporation of precise and personalized diagnostic strategies can enhance patient care, prognosis, and the application and development of targeted therapeutic interventions.

Genetic testing for non-parkinsonian movement disorders: Navigating the diagnostic maze.

Decoding regulatory elements and brain cell-type shifts offers insights into neuropsychiatric disorders.

Many studies have reported metabolomic analysis of different bio-specimens from Parkinson's disease (PD) patients. However, inconsistencies in reported metabolite concentration changes make it difficult to draw conclusions as to the role of metabolism in the occurrence or development of Parkinson's disease. We reviewed the literature on metabolomic analysis of PD patients. From 74 studies that passed quality control metrics, 928 metabolites were identified with significant changes in PD patients, but only 190 were replicated with the same changes in more than one study. Of these metabolites, 60 exclusively increased, such as 3-methoxytyrosine and glycine, 54 exclusively decreased, such as pantothenic acid and caffeine, and 76 inconsistently changed in concentration in PD versus control subjects, such as ornithine and tyrosine. A genome-scale metabolic model of PD and corresponding metabolic map linking most of the replicated metabolites enabled a better understanding of the dysfunctional pathways of PD and the prediction of additional potential metabolic markers from pathways with consistent metabolite changes to target in future studies.

Identification of metabolites reproducibly associated with Parkinson's Disease via meta-analysis and computational modelling.

The genetic architecture of Parkinson's disease (PD) comprises five autosomal dominantly inherited forms with a clinical picture overall resembling idiopathic disease (PARK-, PARK-, PARK-, PARK-, and PARK-) and three recessive types (PARK-, PARK-, and PARK-), several monogenic forms causing atypical parkinsonism, as well as a plethora of known genetic risk factors, most notably  and  including a recently discovered risk variant unique to individuals of African descent, as well as polygenic scores. The Movement Disorder Society Genetic mutation database (MDSGene) (www.mdsgene.org) provides PD genotype-phenotype relationships, whereas global PD genetics networks, such as the Global Parkinson's Genetics Program (www.gp2.org) elucidate PD genetic factors at an unprecedented scale. Two large studies in relatively unselected, multicenter PD samples estimate the frequency of genetic forms, including PARK-, at ∼15%. PD genetics are becoming increasingly actionable, with the first gene-targeted clinical trials underway. Furthermore, PD genetics has recently been incorporated into a new biological classification of PD.

Genetics of Parkinson's Disease: From Causes to Treatment.

Knowledge on the genetic basis of Parkinson's disease has grown tremendously since the discovery of the first monogenic form, caused by a mutation in α-synuclein, and with the subsequent identification of multiple other causative genes and associated loci. Genetic studies provide insights into the phenotypic heterogeneity and global distribution of Parkinson's disease. By shedding light on the underlying biological mechanisms, genetics facilitates the identification of new biomarkers and therapeutic targets. Several clinical trials of genetics-informed therapies are ongoing or imminent. International programmes in populations who have been under-represented in Parkinson's disease genetics research are fostering collaboration and capacity-building, and have already generated novel findings. Many challenges remain for genetics research in these populations, but addressing them provides opportunities to obtain a more complete and equitable understanding of Parkinson's disease globally. These advances facilitate the integration of genetics into the clinic, to improve patient management and personalised medicine.

Uncovering the genetic basis of Parkinson's disease globally: from discoveries to the clinic.

Initial biological classification of Lewy body diseases: No consensus on terminology.

BackgroundThe availability of deep brain stimulation (DBS), a highly efficacious treatment for several movement disorders, remains low in developing countries, with scarce data available on utilization and outcomes.ObjectiveWe characterized the DBS cohort and outcomes at a Malaysian quaternary medical center.MethodsA retrospective chart review was done on DBS-related surgery at the University of Malaya, including clinico-demographic, genetics, and outcomes data focusing on post-operative medication reduction and complications.Results149 Parkinson's disease (PD) patients underwent DBS targeting the subthalamic nucleus. Six had globus pallidus internus DBS (primarily for dystonia). Only 16.1% of patients were government-funded. Of the 133 PD patients operated in the past decade (2013-2022), 25 (18.8%) had disease duration <5 years. At 6-12 months post-DBS, median levodopa-equivalent daily dose (LEDD) reduction was 440.5 [418.9] mg/day, corresponding to a reduction of ≥50% and ≥30% in 42.2% and 69.8% of patients, respectively. LEDD reductions were larger in the early-onset and short-duration subgroups. Three patients (1.9% of 155) had symptomatic intracranial hemorrhage, resulting in stroke in two. Pathogenic monogenic or  variants were detected in 12/76 (16%) of patients tested, mostly comprising the "severe"  variant p.L483P (12%).ConclusionsThis is the largest report on DBS from Southeast Asia. The procedures were effective, and complication rates on par with international norms. Our study found a high frequency of -PD; and included a substantial number of patients with short-duration PD, who had good outcomes. It also highlights regional inequities in access to device-aided therapy.

Article	Year
Neurological symptoms and complications in predominantly hospitalized COVID-19 patients: Results of the European multinational Lean European Open Survey on SARS-Infected Patients (LEOSS). European journal of neurology\| PubMed ID: 34411383	2021
Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency. Autophagy\| PubMed ID: 35030052	2022
Let's make science, not war! Science advances\| PubMed ID: 36260684	2022
Genetic Testing for and Mutations: Is it Time for Routine Use? Movement disorders clinical practice\| PubMed ID: 37637988	2023
Genetic testing for non-parkinsonian movement disorders: Navigating the diagnostic maze. Parkinsonism & related disorders\| PubMed ID: 38429185	2024
Decoding regulatory elements and brain cell-type shifts offers insights into neuropsychiatric disorders. Science advances\| PubMed ID: 38781325	2024
Identification of metabolites reproducibly associated with Parkinson's Disease via meta-analysis and computational modelling. NPJ Parkinson's disease\| PubMed ID: 38951523	2024
Genetics of Parkinson's Disease: From Causes to Treatment. Cold Spring Harbor perspectives in medicine\| PubMed ID: 39134389	2025
Uncovering the genetic basis of Parkinson's disease globally: from discoveries to the clinic. The Lancet. Neurology\| PubMed ID: 39447588	2024
Initial biological classification of Lewy body diseases: No consensus on terminology. Alzheimer's & dementia : the journal of the Alzheimer's Association\| PubMed ID: 39732512	2025
New insights from a Malaysian real-world deep brain stimulation cohort. Journal of Parkinson's disease\| PubMed ID: 39973484	2025

Christine Klein

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