Our research is aimed at identifying molecular and cellular mechanisms underlying the pathogenesis of Amyotrophic lateral sclerosis (ALS). ALS is a clinically and genetically heterogeneous adult onset neurodegenerative disease characterized by the degeneration of motor neurons resulting in paralysis of limb, facial and respiratory muscles, and usually leading to death within 3 years after diagnosis. Currently there is no effective treatment, and there is very little knowledge about the mechanisms underlying sporadic ALS, representing the majority of the cases. A minority of ALS patients (10%) show Mendelian inheritance, and to date more than 10 loci associated with ALS and ALS-like diseases have been identified. A subset of familial ALS patients have mutations in the Cu/Zn superoxide dismutase (SOD1) gene that cause toxic SOD1 aggregates in neurons and glia. Other mutations have been found in p150 dynactin subunit of the dynein-dynactin motor complex, alsin (ALS2), senataxin (ALS4), and vesicle-associated membrane protein B (VAP-B, ALS8).

To unravel ALS disease mechanisms, we are studying cellular and mouse models carrying ALS mutations. A dominant approach in mouse models is the use of confocal and immuno-electron microscopy to precisely characterize neuropathological and molecular changes that precede motoneuron degeneration in vivo.

Ongoing project include:

• Characterisation of neuron-specific and ubiquitous ALS-mutant SOD1 transgenic mouse models to determine cell autonomous and non-cell autonomous toxic actions of mutant SOD1 on motor neurons.
• Analysis of the functions of wild-type and ALS-mutant VAPB in cellular and transgenic mouse models.
• Characterisation of the role of abnormalities in dynein-dependent trafficking in ALS pathogenesis using transgenic mouse models with chronically impaired dynein-dependent trafficking.

Homepage of Dick Jaarsma 

Selected recent publications

• Teuling E, Ahmed S, Haasdijk E, Demmers J, Steinmetz MO, Akhmanova A, Jaarsma D, Hoogenraad CC (2007) Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. J Neurosci. 27: 9801-9815 (Pubmed).
• Vlug AS, Teuling E, Haasdijk ED, French P, Hoogenraad CC, Jaarsma D (2005) ATF3 expression precedes death of spinal motoneurons in amyotrophic lateral sclerosis-SOD1 transgenic mice and correlates with c-Jun phosphorylation, CHOP expression, somato-dendritic ubiquitination and Golgi fragmentation. Eur J Neurosci. 22: 1881-1894 (Pubmed).
• Maatkamp A, Vlug A, Haasdijk E, Troost D, French PJ, Jaarsma D. (2004) Decrease of Hsp25 protein expression precedes degeneration of motoneurons in ALS-SOD1 mice. Eur J Neurosci. 20: 14-28 (Pubmed).
• Jaarsma D, Rognoni F, Van Duijn W, Verspaget H, Haasdijk ED and Holstege JC (2001) CuZn superoxide dismutase (SOD1) accumulate in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis (ALS)-linked SOD1 mutations. Acta Neuropathol. 102: 293-305.(Pubmed)
• Jaarsma D, Haasdijk E, Grashorn JAC, Van Duijn W, Verspaget H, London J and Holstege JC (2000) Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial degeneration, axonal degeneration and premature motoneuron death, and accelerates the development of motoneuron disease in mice expressing fALS-mutant SOD1. Neurobiol Dis. 7: 623-643 (Pubmed)
• Sillevis Smitt P, Kinoshita A, De Leeuw B, Moll W, Coesmans M, Jaarsma D, Henzen-Logmans S, Vecht C, De Zeeuw C, Sekiyama N, Nakanishi S and Shigemoto R (2000) Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med, 342  21-27 (Pubmed)