Significant progress has been made over the past two decades on the pathogenesis of individual neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as well as their distinct neurodegenerative processes. However, different neurodegenerative syndromes have been mainly studied mechanistically in isolation. There has been a lack of concerted effort to ascertain whether and how these pathogenic processes may be linked to one another. Recently, we have detected cryptic exon incorporation in Alzheimer’s disease cases exhibiting TDP-43 pathology. This is the first evidence that loss of TDP-43 function from neurons, a common shared feature with ALS and FTD, could contribute to pathogenesis of AD. It has been known for years that other factors besides Aβ and tau also contribute to neurodegeneration and cognitive failure in AD. The most convincing evidence is that 20-40% of cognitively normal older individuals have levels of Aβ and tau pathology that are indistinguishable from patients with severe clinical symptoms of AD. Recent work showed that non-canonical pathologies occur in up to 75% of AD cases including TDP-43 proteinopathy, α-synuclein “Lewy bodies”, and tau “Pick bodies” that are associated with neurodegeneration in separately classified diseases. TDP-43 proteinopathy is characterized by cytoplasmic aggregation of the transactivation response element DNA-binding protein 43 (TDP-43) accompanied by its nuclear clearance, and was first identified in another neurodegenerative disease spectrum, ALS-FTD. Identified as an essential gene, TDP-43 is also required for aspects of neuronal physiology in mice, fruit flies and zebrafish. Notably, TDP-43 proteinopathy is one of the most common non-canonical pathologies observed in AD cases and is strongly associated with worsened neurodegeneration and cognition, suggesting a convergent mechanism of neurodegeneration with ALS and FTD. We have found that cryptic exon incorporation occurred in all AD cases exhibiting TDP-43 pathology. Furthermore, incorporation of cryptic exons was observed in the hippocampus when TDP-43 inclusions was restricted only to the amygdala, the earliest stage of TDP-43 progression. Most importantly, cryptic exon incorporation could be detected in AD brains lacking TDP- 43 inclusion but exhibiting nuclear clearance of TDP-43. These data supports the notion that the functional consequence of nuclear depletion of TDP-43 as determined by cryptic exon incorporation likely occurs as an early event of TDP-43 proteinopathy and may have greater contribution to the pathogenesis of AD than currently appreciated. This study has opened new direction in AD research as early detection and effective repression of cryptic exons in AD patients may offer important diagnostic and therapeutic implications for this devastating illness of the elderly.

Another ongoing project in our laboratory is studying traumatic brain injury. Chronic traumatic encephalopathy (CTE) is a distinct neurodegenerative disease that is closely associated with exposure to repetitive mild traumatic brain injury (mTBI). The mechanisms responsible for its complex pathologic changes remain largely elusive despite a recent consensus to define the neuropathological criteria. We have established a novel model of CTE in Drosophila melanogaster in attempt to identify the key genes and pathways that lead to the characteristic hyperphosphorylated tau accumulation and neuronal death in brain. Adjustable force to inflict mild closed injury is delivered to fly head directly that subjects the head to rapid acceleration and deceleration. Our method eliminates the potential problems inherent with other Drosophila mTBI models that animal death might be caused by damage to other parts of the body or internal organs. The less labor- and cost-intensive animal care, short life span, make fruit fly ideal to study CTE pathogenesis and make it possible to perform large-scale genome-wide forward genetic and pharmalogical screens. We anticipate that ongoing characterization of our CTE model will generate important mechanistic insights for disease prevention and therapeutic approaches.

Loss of TDP-43 nuclear expression in early Alzheimer’s disease brain video

Making a Drosophila model to study chronic traumatic encephalopathy.