Biology subjects

Cookson, M. R.

Publications and source records attributed to Cookson, M. R..

59 records · Page 4Linked to original sources

bioRxiv2020

Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at Chr16q11.2 and on the MAPT H1 allele.

Parkinsons disease (PD) is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies (GWAS) has considerably advanced our understanding of the PD genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial PD, but its relevance to idiopathic PD is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through GWAS. We identified two new regulators of PINK1-mitophagy, KAT8 and KANSL1, previously shown to modulate lysine acetylation. We show that KAT8 and KANSL1 modulate PINK1 gene expression and subsequent PINK1-mitophagy. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic PD. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data does not exclude a possible association between the MAPT gene and PD, it provides strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.

neuroscience↗

bioRxiv2019

Mutations in Auxilin cause parkinsonism via impaired clathrin-mediated trafficking at the Golgi apparatus and synapse

Parkinsons disease (PD) is a common neurodegenerative motor disorder characterized in part by neuropathological lesions in the nigrostriatal pathway. Loss of function mutations in Auxilin, the major neuronal clathrin uncoating protein, cause an aggressive form of juvenile onset PD. How mutations in Auxilin cause PD, is currently not understood. Here, we generated a novel mouse model carrying an endogenous pathogenic Auxilin mutation that phenocopies neurological features observed in patients, including motor impairments and seizures. Unbiased mapping of the Auxilin interactome identified synaptic and Golgi-resident clathrin adaptor proteins as novel interactors. Impaired clathrin-mediated trafficking in mutant Auxilin mice, both at the Golgi and the synapse, results in neuropathological lesions in the nigrostriatal pathway. Collectively, these results provide molecular mechanisms of PD pathogenesis in Auxilin mutation carriers, reinforcing a key role for clathrin-mediated trafficking in PD, and expand our understanding of the cellular function of Auxilin.

neuroscience↗

bioRxiv2019

Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation

Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of childhood motor disorder with a heterogeneous clinical presentation. The underlying causes of this condition are poorly understood, hindering the development of effective therapies. In a whole-exome sequencing trio-family study of three unrelated juvenile patients diagnosed with ALS and failure to thrive, we identified de-novo mutations in SPTLC1 (p.Ala20Ser in two patients and p.Ser331Tyr) not present in their healthy parents or siblings. SPTLC1 encodes a subunit of the serine palmitoyltransferase complex, a key enzyme in sphingolipid biosynthesis. Mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A, with a characteristic increase in plasma levels of neurotoxic deoxymethyl-sphinganine. We found an increase of this metabolite in one of our patients carrying the p.Ala20Ser mutation. Treatment of one of the patients with high dose, oral L-serine led to an increase in body weight, suggesting that serine supplementation may be beneficial among patients carrying mutations in this gene.

genetics↗

bioRxiv2019

A revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanisms

Leucine-rich repeat kinase 2 (LRRK2) is a large 286 kDa multi-domain protein whose mutation is a common cause of Parkinsons disease (PD). One of the common sites of familial PD-associated mutations occurs at residue Arg-1441 in the GTPase domain of LRRK2. Previously, we reported that the PD-associated mutation R1441H impairs the catalytic activity of the GTPase domain thereby traps it in a persistently \"on\" state. More recently, we reported that the GTPase domain of LRRK2 exists in a dynamic dimer-monomer equilibrium where GTP binding shifts it to the monomeric conformation while GDP binding shifts it back to the dimeric state. We also reported that all of the PD-associated mutations at Arg-1441, including R1441H, R1441C, and R1441G, impair the nucleotide-dependent dimer-monomer conformational dynamics of the GTPase domain. However, the mechanism of this nucleotide-dependent conformational dynamics and how it is impaired by the mutations at residue Arg-1441 remained unclear. Here, we report a 1.6 [A] crystal structure of the GTPase domain of LRRK2. Our structure has revealed a dynamic switch region that can be differentially regulated by GTP and GDP binding. This nucleotide-dependent regulation is impaired when residue Arg-1441 is substituted with the PD-associated mutations due to the loss of its exquisite interactions consisting of two hydrogen bonds and a {pi}-stacking interaction at the dimer interface.\n\nSignificance StatementMutations in LRRK2 are associated with familial Parkinsons disease, so understanding its mechanism of actions and how they are changed by the disease-associated mutations is important for developing therapeutic strategies. This paper describes an atomic structure of the G-domain of LRRK2 revealing that the conformational dynamics of the switch regions are potentially important for its normal function. It further shows that a disease-associated mutation could lock the G domain in a persistently active-like conformation, thus perturbing its normal function.

biochemistry↗

bioRxiv2018

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

The {varepsilon}4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimers disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of A{beta}, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of the APOE4s role in AD pathogenesis, we performed a multi-omic analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. These studies revealed region-specific alterations in several bioenergetic pathways, including oxidative phosphorylation (OxPhos), the TCA-cycle and fatty acid metabolism. Follow-up analysis utilizing the Seahorse platform revealed decreased mitochondrial respiration in the hippocampus and cortex of aged APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original multi-omic data suggest that bioernergetic pathways in the EC of aged APOE mice may be differentially regulated by APOE4 expression. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, this differential bionenergetic regulation observed in the EC vs. other brain regions of aged APOE4 mice may play an important role in the pathogenesis of AD, particularly among APOE4 carriers.

neuroscience↗