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 1.Amyotrophic lateral sclerosis and Frontotemporal lobar degeneration

Amyotrophic lateral sclerosis(ALS) is characterized by progressive weakness, atrophy, fasciculation and wasting of the affected muscles. The characteristic pathologic findings are loss of both lower and upper motor neurons as well as corticospinal tract involvement. ALS is a disease of unknown cause and pathogenesis. The specific histological structures of ALS are Bunina body and skein-like inclusions (ubiquitin-immunoreactive inclusions) in both upper and lower motor neurons. Frontotemporal lobar degeneration (FTLD) or frontotemporal dementia primarily affects the frontal and temporal lobes of the brain where are generally associated with personality and behavior. In people under age 60, FTLD is the most common cause of dementia and affects as many people as Alzheimer’s disease in the 45-64 age group. Subtyping, including Behavioral variant FTD (bvFTD), Semantic dementia (SD) and Progressive nonfluent aphasia (PNFA),  is based on the distinct patterns of signs and symptoms.

An important recent advance has been the finding of inclusion bodies consisting of abnormally phosphorylated proteins in residual motor neurons detected by immunohistochemical staining for TAR DNA-binding protein of 43kDa (TDP-43), tau and FUS (Fused in sarcoma). These proteins are major components of the aggregates and inclusions that characterize ALS and FTLD, referred to as FTLD-TDP,FTLD-tau and FTLD-FUS. Mutations in these genes gave strong support to the notion that accumulation of TDP-43, tau and FUS are a fundamental molecular pathology of the most common forms of FTLD and motor neuron disease. There exists considerable clinical and pathological overlap between FTLD and ALS, which implies that these 2 neurodegenerative conditions are part of a disease spectrum that is clinically, pathologically, and genetically heterogeneous.

Our laboratory studies the mechanism of aggregation formation of TDP-43, tau and FUS and neuronal death in the ALS/FTLD spectrum of neurodegenerative disease. The other theme of our research is to get an insight into the mechanisms responsible for the selective motor neuronal death during ALS/FTLD. Furthermore, we have investigated the interaction between TDP-43 and tau as the major component of neurofibrillary tangles in ALS/Parkinsonism dementia-complex (PDC) of Guam.


2. Multiple system atrophy

Multiple system atrophy (MSA) is a neurodegenerative disorder that develops in adulthood, usually in the 50s or 60s. MSA is characterized by a combination of symptoms that affect both the movement and autonomic nervous system. Motor dysfunction includes symptoms such as tremor, rigidity, and loss of muscle coordination. Some of these symptoms are similar to those seen in Parkinson’s disease. Dysfunction of autonomic nervous system includes fainting spells, problems with heart rate and digestion, and loss of bladder control. MSA is associated with atrophy of portions of the cerebellum, basal ganglia and brainstem that regulate internal body functions, digestion and motor control. Pathological findings with MSA reveals neurons that contain an abnormal amount ofα-synuclein. Some research suggests that this protein may be overexpressed in MSA. The argyrophilic glial cytoplasmic inclusions (GCIs) in the oligodendrocytes of patients with MSA consist of α-synuclein. α-synuclein is also an important component of the Lewy bodies in Parkinson's disease and dementia with Lewy bodies. Subsequently, similar inclusions were identified in glial nuclei (glial nuclear inclusions (GNIs)), and in neuronal cytoplasm and nuclei (neuronal cytoplasmic inclusions (NCIs), and neuronal nuclear inclusions (NNIs), respectively), and also in axons. However, the mechanisms underlying these abnormal accumulation ofα-synuclein, and how it relates to glial and neuronal loss in MSA, remain to be determined. Understanding these processes will be essential before an effective treatment to modify the disease course can be found.