Dysregulation of Stathmin, a Microtubule-Destabilizing Protein, and Up-Regulation of Hsp25, Hsp27, and the Antioxidant Peroxiredoxin 6 in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

Abstract

Gain-of-function mutations of the Cu/Zn superoxide dismutase (SOD1) gene cause dominantly inherited familial amyotrophic lateral sclerosis. The identification of differentially regulated proteins in spinal cords of paralyzed mice expressing SOD1(G93A) may contribute to understanding mechanisms of toxicity by mutant SOD1. Protein profiling showed dysregulation of Stathmin with a marked decrease of its most acidic and phosphorylated isoform, and up-regulation of heat shock proteins 25 and 27, peroxiredoxin 6, phosphatidylinositol transfer protein-alpha, apolipoprotein E, and ferritin heavy chain. Stathmin accumulated in the cytoplasm of 30% of spinal cord motor neurons with fragmented Golgi apparatus. Overexpression of Stathmin in HeLa cells was associated with collapse of microtubule networks and Golgi fragmentation. These results, together with the decrease of one Stathmin isoform, suggest a role of the protein in Golgi fragmentation. Mutant SOD1 co-precipitated and co-localized with Hsp25 in neurons and astrocytes. Mutant SOD1 may thus deprive cells of the anti-apoptotic and other protective activities of Hsp25. Astrocytes contained peroxiredoxin 6, a unique nonredundant antioxidant. The up-regulation of peroxiredoxin 6 probably constitutes a defense to oxidative stress induced by SOD1(G93A). Direct effects of SOD1(G93A) or sequential reactions triggered by the mutant may cause the protein changes.

Induction of the Unfolded Protein Response in Familial Amyotrophic Lateral Sclerosis and Association of Protein-disulfide Isomerase with Superoxide Dismutase 1

“…Spot 13 was increased up to 7-fold and identified as PDI, with 36% coverage by MALDI-TOF-MS. Spot 14 was characterized as Erp57, a second member of the PDI family, increased up to 6-fold, with 39% coverage by MALDI-TOF-MS analysis. A previous proteomic study did not identify the differential regulation of PDI family members (33). However, pooled tissue extracts were used that may mask identification of some proteins, and SOD1 G93A mice were used instead of rats.…”

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

“…In the SOD1 mouse model of ALS, although there is a general increase in hsp27 and hsp70 levels in the spinal cord during disease progression, hsp27 is virtually absent from motoneuron cell bodies in symptomatic mice [5]. Similarly, it has also been shown that hsp25 immunoreactivity is present in motoneurons of presymptomatic but not symptomatic SOD1 mice [36]. In vitro, the combination of hsp40 and hsp70 overexpression has been shown to be protective against mutant SOD1-induced cell death [23].…”

Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration

“…Disturbances of neuronal transport have been suggested as potential causal factors in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Data from cell cultures and preclinical models suggest that abnormal microtubule (MT) dynamics and MT-based neuronal transport may play a role (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”