Catalog

ASAP is committed to accelerating the pace of discovery and informing a path to a cure for Parkinson’s disease through collaboration, research-enabling resources, and data sharing. We’ve created this catalog to showcase the research outputs and tools developed by ASAP-funded programs.

Article

Structural basis for the specificity of PPM1H phosphatase for Rab GTPases

Published: LRRK2 acts by adding a phosphate group to enzymes known as Rab GTPases, which causes new biological events. The authors analyzed the structure of an enzyme, PPM1H, that counteracts LRRK2 by removing the phosphate group it adds to Rab GTPases. View original preprint.

Article

Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain

Published: Pathogenic mutations in LRRK2 are known to cause loss of primary cilia in neurons. The authors show that cilia loss is seen very early in mice harboring the most common LRRK2 mutation. Further, they show that this loss of cilia in astrocytes disrupted signaling pathways required for dopamine neuron maintenance. View original preprint.

Article

Impact of 100 LRRK2 variants linked to Parkinson’s Disease on kinase activity and microtubule binding

Published: LRRK2 is a promising candidate for PD therapeutics via reduction of its kinase activity. The authors investigated 98 LRRK2 variants and their effects on function. They found 22 variants that robustly stimulated LRRK2 kinase activity and 12 variants that suppressed microtubule association in the presence of Type 1 kinase inhibitors. View original preprint.

Article

A feed-forward pathway drives LRRK2 kinase membrane recruitment and apparent activation

Published: Mutations in LRRK2 that cause PD activate its kinase activity. These activating mutations of LRRK2 phosphorylate Rab GTPases. The authors define two binding sites on LRRK2 that deliver it to the surfaces of specific intracellular membranes, and then retain it there after an initial phosphorylation event. View original preprint here.

Article

Global ubiquitylation analysis of mitochondria in primary neurons identifies physiological Parkin targets following activation of PINK1

Published: Mutations in PINK1 and Parkin are implicated in PD via abherrant mitophagy. The authors identified ubiquitylated substrates of endogenous Parkin in mouse neurons by proteomic analysis. They identified and validated 22 protein targets of Parkin that are conserved in human neurons providing a functional Parkin landscape in neuronal cells. View original preprint.

Article

Structural basis of human LRRK2 membrane recruitment and activation

Published: LRRK2 kinase activating mutations are the most common genetic cause of PD. Rab29, a membrane-anchored GTPase, regulates LRRK2’s kinase activity and brings it to the Golgi. The authors report cryo-EM structures of LRRK2-Rab29 complexes in three oligomeric states illustrating LRRK2 membrane recruitment and activation. View original preprint.

Article

Isotope tracing in health and disease

Here, the authors review recent work utilizing metabolic tracing to study health and disease, and highlight its application to interrogate subcellular, intercellular, and in vivo metabolism. The authors further discuss the current challenges and opportunities to expand the utility of isotope tracing to new research areas.

Article

“LRRK2 phosphorylation of Rab GTPases in Parkinson’s disease”

Review: This paper highlights new findings related to LRRK2-mediated phosphorylation of Rab GTPases and their consequences.

Article

PTEN-induced kinase 1 (PINK1) and Parkin: Unlocking a mitochondrial quality control pathway linked to Parkinson’s disease

Review: This review focuses on understanding the PINK1/Parkin-mediated mitochondrial quality control pathway through the lens of abherrant immune activation as a driver of dopaminerigic neuron loss following the loss of PINK and Parkin.

Article

Golgi-IP, a novel tool for multimodal analysis of Golgi molecular content

Published: Traditional methods are too slow to preserve the labile Golgi metabolome and transient protein interactions. Here, the authors develop a method for the rapid capture of intact Golgi from human cells via Golgi immunoprecipitation (Golgi-IP). Using high-resolution mass spectrometry, the approach allows the unbiased characterization of the Golgi proteome, metabolome, and lipidome.
 

Article

Global ubiquitylation analysis of mitochondria in primary neurons identifies endogenous Parkin targets following activation of PINK1

Published: Loss-of-function mutations in Parkin cause disruption of mitophagy and are associated with PD. Yet, much of the biology surrounding Parkin function has taken place in artificial cell systems. The authors used human neurons to identify and validate 22 protein targets of Parkin, providing a functional Parkin landscape in neuronal cells.

Article

PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074, and Thr1075) within the CORB GTPase domain

Leucine-rich-repeat-kinase 1 (LRRK1) and its homologue LRRK2 are multidomain kinases possessing a ROC-CORA-CORB containing GTPase domain and phosphorylate distinct Rab proteins. LRRK1 loss of function mutations cause the bone disorder osteosclerotic metaphyseal dysplasia, whereas LRRK2 missense mutations that enhance kinase activity cause PD. Here, the authors study the mechanism controlling LRRK1 activity and reveal a novel unexpected activation mechanism. View preprint.

Article

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

Published: The data supports a model in which 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. View original preprint.

Article

Role of autophagy pathway in Parkinson’s disease and related genetic neurological disorders

The authors provide a comprehensive overview of the general importance of autophagy in Parkinson’s disease (PD) and related disorders of the central nervous system (CNS). This reveals a critical link between autophagy and neurodegenerative and neurodevelopmental disorders and suggests that strategies to modulate mitophagy may have greater relevance in the CNS beyond PD.