ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma).

Basic Science and Pathogenesis.

Background: Severe systemic infections can trigger cognitive decline, but the underlying mechanisms and their impact on the manifestation and progression of Alzheimer's disease and other neurodegenerative diseases are poorly understood. The current COVID-19 pandemic has brought a surge of severe viral illness and highlights the importance of understanding the impact of acute infections on cognition and the manifestation of neurodegenerative disease in survivors. A wealth of observational and clinical data suggests major short- and long-term effects of severe infections on cognition, but detailed and systematic analyses of neuropathological changes after acute infections are scarce.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease, and it is characterized by aggregation of misfolded proteins in the brain. Intraneuronal accumulation of tau pathology form neurofibrillary tangles (NFT) in AD. The assessment of the severity of intraneuronal inclusions holds significance in studying the clinicopathological associations in neurodegenerative diseases.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is one of the leading causes of death among seniors in the United States and costs the nation over $300 billion each year. Neuropathologically, AD is characterized by neuronal loss, Aβ deposits in the form of plaques, and intracellular aggregates of tau protein in the form of neurofibrillary tangles (NFT). The amyloid cascade hypothesis, one of the leading hypotheses of AD pathogenesis, suggests that Aβ aggregates are directly neurotoxic, triggering downstream neurodegeneration.

Basic Science and Pathogenesis.

Background: Limbic predominant age-related TDP-43 encephalopathy (LATE) is a common co-pathology in Alzheimer's disease (AD) and is associated with advanced cognitive impairment and severe atrophy in limbic regions. In AD, various maturation stages for tau neurofibrillary tangles have been characterized and can be selectively marked by monoclonal tau antibodies, providing insight into disease progression. Indeed, AD tau pathology progresses from an early "paperclip" conformation, marked by the MC1 epitope to a C-terminally truncated form of tau, marked by MN423 epitope.