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PD Functional Genomics

Prior to the launch of the ASAP initiative, Parkinson’s disease research primarily centered on mechanisms involving known risk genes and disrupted pathogenic processes. Genetic advancements over the past decade have shifted focus from single genes to broader genomic changes, resulting in a greater need to better understand effects on organelle and cellular function within the context of the disrupted pathogenic processes. Researchers within the PD Functional Genomics theme use innovative approaches to uncover mechanisms contributing to PD pathogenesis and progression. The research focuses on two major areas:

  • Conducting unbiased analyses of human datasets and models to identify novel targets and mechanisms.
  • Investigating the functional impact of known risk genes (e.g., SNCA, GBA1, LRRK2, PRKN, PINK1) and pathogenic pathways (e.g., mitophagy, lysosomal dysregulation) on disease progression and heterogeneity.

Highlights

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ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

Mutations in ATP13A2 cause a spectrum of related neurodegenerative disorders. ATP13A2 is a lysosomal exporter of polyamines that contributes to lysosomal health and controls cellular polyamine content. Conversely, loss of ATP13A2 leads to lysosomal dysfunction, a hallmark of neurodegeneration. Here, Team Vangheluwe shows that ATP13A2-mediated polyamine transport represents a conserved pathway that protects against mitochondrial oxidative stress.

Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease

Little is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, Team Scherzer systematically identify over 11,039 circRNAs expressed in vulnerable dopamine and pyramidal neurons laser-captured from 190 human brains and non-neuronal cells using ultra-deep, total RNA sequencing. This study shows that circular RNAs in the human brain are tailored to neuron identity and implicate circRNA-regulated synaptic specialization in neuropsychiatric diseases.

The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1

Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson’s disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. Teams Hardy and Wood show findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.

Genome-wide screen reveals Rab12 GTPase as a critical activator of Parkinson’s disease-linked LRRK2 kinase

Activating mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases, particularly Rab10 and Rab8A, and it had been shown previously that these phosphoRabs play an important role in LRRK2 membrane recruitment and activation. Team Alessi shows that Rab12 binding to a new site in the LRRK2 Armadillo domain activates LRRK2 kinase for Rab phosphorylation and could serve as a new therapeutic target for a novel class of LRRK2 inhibitors that do not target the kinase domain.

Our Teams

The focus across these teams will be to unravel the biology underlying genetic mutations associated with Parkinson’s disease.