Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by weakness, muscle atrophy and spasticity related to the selective loss of motor neurons in the cortex, brain stem and spinal cord, is the most common adult motor neuron disease. Approximately 5-10% of ALS cases are familial, and except for mutations in SOD1 that cause a subset of familial ALS, the etiology of ALS is largely unknown. The identification of specific genes causing ALS allows generation of animal models for studies of disease mechanisms to facilitate the design of rationale therapy for treatment of this devastating illness. Recently, a missense mutation (G59S) in a gene encoding the largest subunit of dynactin complex, termed p1509'U8d, was identified in a large family that associates with slowly progressive lower motor neuron disease. Although mutant dynactin p15CPlued alleles are inherited in an autosomal dominant fashion, suggesting that the disease may result from a toxic gain of function, initial in vitro studies indicated that disease linked mutant p150glued possessed a reduced binding efficiency to microtubules, indicating a partial loss of function. To begin to clarify the mechanism whereby mutant p1509lued causes selective motor neuron disease, we plan to take a genetic approach to first generate human wild type and mutant dynactin transgenic mice and characterize the consequences of expression of mutant p1509lued in mice. In addition, we plan to generate and characterize dynactin p150P'ued standard knockout mice by deleting the gene encoding dynactin p1509'UBd. We hypothesize that mutant, but not wild type dynactin p15CPlued mice will lead to clinical and neuropathological outcomes that are consistent with motor neuron disease whereas mice lacking one allele of dynactin p15QPlued are normal. Such outcomes would be consistent with the idea that ALS-linked mutant p1509'ued causes disease through a gain of function mechanism. Finally, since dynactin is involved in axonal transport, we will examine whether mutant dynactin p1509lued impacts on either anterograde or retrograde axonal transport in these wild type and mutant dynactin p15CPluf>d mice. Taken together, these efforts will clarify the mechanism whereby mutant dynactin p15CPlued causes motor neuron disease and will have the potential to identify novel therapeutic targets and allow design of drug treatments for motor neuron disease. [unreadable] [unreadable] [unreadable]