We hypothesize that mutations in the Glucocerebrosidase gene and other lysosomal genes in the same biochemical pathway including Hexosaminidase A (HEXA), Sphingomyelin phosphodiesterase 1 (SMPD1) and mucolipin 1 (MCOLN1) may disrupt the cellular processing and trafficking of a-Synuclein and lead to Lewy Body formation. In our previous study, R21, NS050487, we have shown that mutations in the glucocerebrosidase gene are risk factors for PD and Lewy body disease. In the current application we propose to continue our studies on the GBA gene and will examine three additional lysosomal genes, mutations in which cause lysosomal storage disorders, namely, HEXA (Tay Sachs), SMPD1 (Niemann Pick Type A and B) and MCOLN1 (Mucolipidosis type IV) in clinically characterized PD patients and controls and LBD brain bank samples. There are two specific aims.
In Aim1 we will identify genetic variation in 4 lysosomal including GBA, HEXA, SMPD1 and MCOLN1. First, for initial gene analysis, we will use a discovery set from the NY Ashkenazi Jewish study consisting of 300 cases and 300 controls (NY AJ, NS50487). We have chosen Ashkenazi Jewish cases and controls as a discovery set because it is a genetically homogeneous population and is likely to be more powerful than other admixed populations. Second, We will use a replication set from GEPD NS36630 and CORE PD NS36630 that comprises 1504 cases and 314 controls which will be used to examine allelic association of variants identified in the discovery set. Third, for alleles that are significant in the replication set we will combine the discovery and replication sets to estimate risk. The goal of Aim 2 is to further characterize Lewy Body brain autopsy samples. First, we will identify additional mutation carriers in additional Lewy body cases that are available in the NYBB. Second, We will measure enzyme activity (GBA, HEXA, SMPD1) or mRNA levels in addition to sphingolipid accumulation in neuropathologically defined Lewy body cases with lysosomal gene mutations compared to Lewy body cases without mutations and controls. Second, neuropathological evaluation of Lewy body brain autopsy samples with and without mutations will include quantitative and qualitative evaluation of a-synuclein positive structures in cortex, SN, hippocampus and cerebellum.

Public Health Relevance

Significantly, recent studies suggest that mutations in lysosomal genes may be associated with PD and the lysosomal/autophagic pathway has also been implicated in PD pathogenesis. This study will serve to clarify the role of lysosomal genes in genetic susceptibility to PD. ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS060113-01A1
Application #
7581690
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Sutherland, Margaret L
Project Start
2008-09-29
Project End
2012-08-30
Budget Start
2008-09-29
Budget End
2009-08-30
Support Year
1
Fiscal Year
2008
Total Cost
$350,656
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74
Mirelman, Anat; Saunders-Pullman, Rachel; Alcalay, Roy N et al. (2018) Application of the Movement Disorder Society prodromal criteria in healthy G2019S-LRRK2 carriers. Mov Disord 33:966-973
Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:
Kun-Rodrigues, Celia; Ross, Owen A; Orme, Tatiana et al. (2017) Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies. Neurobiol Aging 49:214.e13-214.e15
Guerreiro, Rita; Escott-Price, Valentina; Darwent, Lee et al. (2016) Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging 38:214.e7-214.e10
Louis, Elan D; Clark, Lorraine; Ottman, Ruth (2016) Familial Aggregation and Co-Aggregation of Essential Tremor and Parkinson's Disease. Neuroepidemiology 46:31-6
Baskovich, Brett; Hiraki, Susan; Upadhyay, Kinnari et al. (2016) Expanded genetic screening panel for the Ashkenazi Jewish population. Genet Med 18:522-8
Liu, Xinmin; Hernandez, Nora; Kisselev, Sergey et al. (2016) Identification of candidate genes for familial early-onset essential tremor. Eur J Hum Genet 24:1009-15
Alcalay, Roy N; Mejia-Santana, Helen; Mirelman, Anat et al. (2015) Neuropsychological performance in LRRK2 G2019S carriers with Parkinson's disease. Parkinsonism Relat Disord 21:106-10
Saunders-Pullman, Rachel; Alcalay, Roy N; Mirelman, Anat et al. (2015) REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers. Mov Disord 30:1834-9

Showing the most recent 10 out of 36 publications