(mentions CMT 2) Seipinopathy: a novel endoplasmic reticulum stress-associated

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Brain. 2008 Sep 12.

Seipinopathy: a novel endoplasmic reticulum stress-associated disease.

Ito D, Suzuki N.

Department of Neurology, School of Medicine, Keio University, 35

Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

The Seipin/BSCL2 gene was originally identified as a loss-of-function

gene for congenital generalized lipodystrophy type 2 (CGL2), a

condition characterized by severe lipoatrophy, insulin resistance,

hypertriglyceridaemia and mental retardation. Recently, gain-of-toxic-

function mutations (namely, mutations N88S and S90L) in the seipin

gene have been identified in autosomal dominant motor neuron diseases

such as Silver syndrome/spastic paraplegia 17 (SPG17) (OMIM #270685)

and distal hereditary motor neuropathy type V (dHMN-V) (OMIM

#182960).

Detailed phenotypic analyses have revealed that upper motor neurons,

lower motor neurons and peripheral motor axons are variously affected

in patients with these mutations. The clinical spectrum for these

mutations is broad, encompassing Silver syndrome, some variants of

Charcot-Marie-Tooth disease type 2, dHMNV and spastic paraplegia,

even within a common pedigree.

Therefore, we propose that seipin-related motor neuron diseases can

be collectively referred to as 'seipinopathies'. Expression of the

seipin protein can be detected in motor neurons in the spinal cord

and white matter in the frontal lobe. This is consistent with the

distribution of seipinopathies in the upper and lower motor neurons.

Recent studies have shown that seipin, an endoplasmic reticulum (ER)-

resident membrane protein, is an N-glycosylated protein that is

proteolytically cleaved into N- and C-terminal fragments and is

polyubiquitinated. Interestingly, the N88S and S90L mutations are in

the N-glycosylation motif, and these mutations enhance ubiquitination

and degradation of seipin by the ubiquitin-proteasome system (UPS).

Furthermore, both mutations appear to result in proteins that are

improperly folded, which leads to accumulation of the mutant protein

in the ER. We have shown that expression of mutant forms of seipin in

cultured cells activates the unfolded protein response (UPR) pathway

and induces ER stress-mediated cell death.

These findings suggest that seipinopathies are novel conformational

diseases and that neurodegeneration in these diseases is tightly

associated with ER stress, which has recently been reported to be

associated with other neurodegenerative diseases. Further study of

the pathological mechanisms of the mutant forms of seipin may lead to

important new insights into motor neuron diseases, including other

spastic paraplegia diseases and amyotrophic lateral sclerosis.