Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by degeneration of motor neurons in the brain and spinal cord, eventually leading to respiratory failure and death. ALS affects an estimated 350,000 individuals worldwide, with 50% dying within 3 years of onset. Most ALS cases are sporadic (SALS) of unknown etiology. About 5-10% of ALS cases have a family history (FALS). Mutations in optineurin (OPTN) have been shown to cause ALS in different populations through an unknown mechanism. We have recently shown that OPTN is a common component in the ALS-characteristic skein-like inclusions in the spinal motor neurons of all ALS cases, except for those with SOD1 mutations. Our data, together with those from previous studies of TDP43 and FUS provide important evidence supporting the hypothesis that: (I) most of ALS, including sporadic ALS and SOD1-negative FALS (accounting for approximately 97% of all ALS cases), may share some common elements in the disease pathogenesis, although there is great diversity in the cause~ and (II) the pathogenesis of SOD1-linked ALS (accounting for approximately 3% of all ALS cases) may be largely distinct from the rest of ALS. Currently, there is no effective treatment for ALS. A large number of clinical trials have been carried out, but have failed to show promising results. Some compounds showed therapeutic effect on the SOD1G93A ALS mouse model (the most widely use ALS mouse model for ALS research and drug testing), but not subsequently on ALS patients in clinical trials, possibly due to the difference of pathogenic pathways between SOD1-linked ALS and the rest forms of ALS, as suggested by OPTN, FUS and TDP43 pathological studies. Development of rational and effective therapies for this devastating disease is largely hindered by limited knowledg about its pathogenic mechanism. Pathogenesis of OPTN-linked ALS is largely unknown and its relation to other forms of ALS remains to be elucidated. Our preliminary in vitro data suggest that OPTN and UBQLN2 have a convergent role in autophagy and UPS, and impairment of autophagy and UPS by OPTN and UBQLN2 mutations may contribute to motor neuron degeneration in ALS. OPTN-linked ALS mouse models should be valuable tools for further investigation of the in vivo pathogenic mechanisms. In this application, we propose to develop three mouse models: OPTNWT transgenic, OPTNE478G transgenic and optn knockout (optn-/-) mouse models. We will deposit these mice to the Jackson Laboratories as soon as they are established. Successful completion of this project will be highly likely to provide valuable tools for the research community to study not only the OPTN-linked ALS, but also the convergence of pathogenic mechanisms of sporadic ALS and familial ALS caused by different genetic defects. Moreover, these mouse models may also be used for screening and testing potential therapeutic approaches.
Mutations in optineurin (OPTN) have been shown to cause ALS, but the disease mechanism remains to be elucidated. In this application, we propose to develop and characterize novel OPTN-linked ALS mouse models and make these mouse models available to the research community. Successful completion of this project will provide valuable tools for the research community to study not only the OPTN-linked ALS, but also the convergence of pathogenic mechanisms of sporadic ALS and familial ALS caused by different genetic defects. Moreover, these mouse models may also be used for screening and testing potential therapeutic approaches.
|Gorrie, George H; Fecto, Faisal; Radzicki, Daniel et al. (2014) Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. Proc Natl Acad Sci U S A 111:14524-9|
|Bigio, Eileen H; Wu, Jane Y; Deng, Han-Xiang et al. (2013) Inclusions in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), but not FTLD with FUS proteinopathy (FTLD-FUS), have properties of amyloid. Acta Neuropathol 125:463-5|