Altered functional properties of a TRPM2 variant in Guamanian ALS and PD.
Two related neurodegenerative disorders, Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD), originally occurred at a high incidence on Guam, in the Kii peninsula of Japan, and in southern West New Guinea more than 50 years ago. These three foci shared a unique mineral environment characterized by the presence of severely low levels of Ca(2+) and Mg(2+), coupled with high levels of bioavailable transition metals in the soil and drinking water. Epidemiological studies suggest that genetic factors also contribute to the etiology of these disorders. Here, we report that a variant of the transient receptor potential melastatin 2 (TRPM2) gene may confer susceptibility to these diseases. TRPM2 encodes a calcium-permeable cation channel highly expressed in the brain that has been implicated in mediating cell death induced by oxidants. We found a heterozygous variant of TRPM2 in a subset of Guamanian ALS (ALS-G) and PD (PD-G) cases. This variant, TRPM2(P1018L), produces a missense change in the channel protein whereby proline 1018 (Pro(1018)) is replaced by leucine (Leu(1018)). Functional studies revealed that, unlike WT TRPM2, P1018L channels inactivate. Our results suggest that the ability of TRPM2 to maintain sustained ion influx is a physiologically important function and that its disruption may, under certain conditions, contribute to disease states.
Hermosura
Meredith C
MC
Pacific Biosciences Research Center, University of Hawaii at Manoa, Honolulu, HI 96822, USA. meredith@pbrc.hawaii.edu
Cui
Aaron M
AM
Go
Ramon Christopher V
RC
Davenport
Bennett
B
Shetler
Cory M
CM
Heizer
Justin W
JW
Schmitz
Carsten
C
Mocz
Gabor
G
Garruto
Ralph M
RM
Perraud
Anne-Laure
AL
D000246:Adenosine Diphosphate Ribose / Q000494:pharmacology; D000595:Amino Acid Sequence; D000599:Amino Acids, Diamino / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D017124:Conserved Sequence; D000087522:Cyanobacteria Toxins; D019143:Evolution, Molecular; D006141:Guam; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D007930:Leucine / Q000235:genetics; D008274:Magnesium / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000378:metabolism*; D011392:Proline / Q000235:genetics; D050053:TRPM Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013696:Temperature
D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D050505:Mutant Proteins; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; C001824:beta-N-methylamino-L-alanine; D000246:Adenosine Diphosphate Ribose; D011392:Proline; D006861:Hydrogen Peroxide; D007930:Leucine; D008274:Magnesium; D002118:Calcium