Altered functional properties of a TRPM2 variant in Guamanian ALS and PD

Abstract

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 calciumpermeable 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.calcium ͉ neurodegeneration ͉ oxidative stress ͉ channelopathy ͉ gene environment

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…TRPM2 and TRPM7 are thought to initiate neuronal cell death by sensing oxidative stress (TRPM2 is a redox sensor); indeed, TRPM2 and TRPM7 are crucial for cell viability in neurodegenerative diseases (for a review, see Benarroch, 2008;Szydlowska and Tymianski, 2010). A subset of patients with ALS-G and PD-G are heterozygotes for a missense mutation in the Trpm2 and Trpm7 genes, which cause fast inactivation and increased sensitivity to inhibitory Mg 2+ (Hermosura et al, 2005(Hermosura et al, , 2008Hermosura and Garruto, 2007). It seems that ion influx through both channels is physiologically important, and disruption of this influx may, under certain conditions, contribute to disease states (Hermosura et al, 2008).…”

“…A subset of patients with ALS-G and PD-G are heterozygotes for a missense mutation in the Trpm2 and Trpm7 genes, which cause fast inactivation and increased sensitivity to inhibitory Mg 2+ (Hermosura et al, 2005(Hermosura et al, , 2008Hermosura and Garruto, 2007). It seems that ion influx through both channels is physiologically important, and disruption of this influx may, under certain conditions, contribute to disease states (Hermosura et al, 2008). Because the ALS-G and PD-G environments are deficient in Ca 2+ and Mg…”

“…Loss-of-function TRPM2 (P1018L) and TRPM7 (T1482I) mutants have been linked to PD-G and Western Pacific ALS-G (Hermosura et al, 2005(Hermosura et al, , 2008. The mutant TRPM7 has normal kinase activity but shows increased sensitivity to Mg 2+ blockade.…”

International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family

“…Human genetics studies indicate the potential involvement of TRPM2 in bipolar disorders (McQuillin et al, 2006). In addition, an inactivating proline-to-leucine substitution at position 1018 in TRPM2 is found in two related neurodegenerative disorders, amyotrophic lateral sclerosis and Parkinsonism/dementia complex, that have a high incidence on the Pacific Islands of Guam and Rota (Hermosura et al, 2008).…”

Changes in TRP Channels Expression in Painful Conditions

“…Activation of the TRPM2 channel by oxidative stress, TNF-α and Aβ42 and the resultant loss of neuronal cells strongly suggest a role of these channels in the pathophysiology of Alzheimer's disease [197][198][199]. Altered TRPM2 channel expression and/or function are also reported in several neurological diseases such as stroke, Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia [200].…”