| Summary: | 博士 === 國立清華大學 === 分子與細胞生物研究所 === 101 === Abstract
Amyotrophic lateral sclerosis (ALS) is a complicate and progressive onset devastating neurodegenerative disease. According to the announcement of World Health Organization, it is one of the five most important incurable human diseases of this era, along with cancer and AIDS. Our study showed that average incidence and prevalence of ALS in Taiwan was 0.51 and 1.97 per 105, respectively. Till now, the etiology of ALS remains largely unclear and its diagnosis is difficult; on average 10% misdiagnosis rate for ALS is reported. In addition, the averaged delay period between symptom onset to confirmation of ALS diagnosis may be up to 13 to 18 months. Hence searching for novel molecular biomarkers to improve the clinical diagnostic ability for ALS is essentially important.
Neuroinflammation, glutamate excitotoxicity, altered cytoskeletal proteins, impaired axoplasmic transport, and oxidative stress are involved in the pathogenesis of ALS. Among which oxidative stress plays an important role. Damaged associated molecular patterns (DAMPs) represent potential diagnostic biomarkers for a number of neurodegenerative diseases. In our studies, we found that domain specific monoclonal antibodies against heat shock proteins (HSP60 and HSC70) could successfully detect serum HSPs level in ALS patients and prove the difference between healthy adults and ALS patients. These monoclonal antibodies could be useful molecular biomarkers for the diagnosis of ALS.
Interestingly, serum levels of autoantibody (autoAb) against high mobility group box 1 (HMGB1) in ALS patients were significantly higher as compared with those in patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), and healthy control subjects. Meanwhile, serum levels of HMGB1 autoAb were correlated with ALS disease progression, indicating that HMGB1 autoAb served as an effective molecular biomarker for diagnosis and clinical evaluation of ALS. This biomarker could be used to diagnose early stages of ALS, monitor disease progression, and potentially evaluate therapeutic efficacy during clinical trials. Therefore, identification of these molecular biomarkers could eventually assist understanding of the disease by providing insights into the pathogenesis of ALS.
Investigation of neuroprotective mechanism is important in development of therapeutic strategies for ALS and other neurodegenerative diseases. Deficiency of neurotrophic factors and mitochondrial dysfunction has been implicated in the pathogenesis of ALS, Huntington's disease (HD) and many neurodegenerative diseases. Meanwhile, brain-derived neurotrophic factor (BDNF) is known to rescue neuronal death.
3-Nitropropionic acid (3-NP) is an irreversible inhibitor of mitochondrial succinate dehydrogenase for exploring molecular mechanisms of cell death associated with mitochondrial dysfunction in neurodegenerative diseases. Here primary culture of fetal rat cortical neurons with different treatments of 3-NP and BDNF was studied. We proposed a hypothetical signal transduction pathway potentially inducible by BDNF preconditioning, denoted as: “BDNF → NO →PKG → Thioredoxin → Bcl-2 → protect neurodegeneration”. However, we also found that full protection could not be achieved with these pathway activators, indicating that this proposed pathway is only part of the signaling cascade inducible by BDNF preconditioning.
On the other hand, our other previous studies have also found that preconditioning of neuronal culture with BDNF induced sonic hedgehog (SHH), meanwhile BDNF-dependent SHH expression and 3-NP resistance required prior induction of EPO. Based on these findings, we proposed another hypothetical signal transduction pathway of BDNF signaling cascade, denoted as: "BDNF → EPO → SHH → protect neurodegeneration". In conclusion, all the above findings may illustrate a clue to develop new therapeutic strategy for ALS, HD, and many other neurodegenerative diseases.
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