Neuropathological Features Of Brain Pathologies

Neuropathological features of brain pathologies   Regions of the brain affected: o Caudate/putamen. o Ventrolateral thalamic nucleus. o Subthalamic nucleus. o Substantia nigra. o Globus pallidus. There is a combination of granular and filamentous material (neuronal intranuclear inclusions) that accumulate in the nuclei of the neurons affected. Genetics  Autosomal dominant trait.  First genetic disease to be localised to a chromosomal location (4p16.3).  Genetically homogenous (only one gene causes the disease).  Gene has uninterrupted CAG repeat in exon 1.  Disease when increase in the length of CAG repeats (trinucleotide repeat expansion). Increasing number of repeats  In the lagging strand, there are Okazaki fragments formed that are repetitive CAGs.  Sometimes, CAGs have a higher affinity to other CAGs than their paired bases. This causes a hairpin loop to form.  As a result, the bases are once again unpaired, causing further pairing with more bases.  After another round of cell division (and hence DNA replication), one chromatid will have an extra set of bases and hence code for a longer code of DNA (with more CAG repeats).    Problem is posed if it is passed on to successive generations, with more CAG repeats being added on each time. Link to Huntington’s disease: o CAG codes for glutamine. o Polyglutamine stretch probably facilitates binding of a number of proteins. o Extended polyglutamine tracts misfold and form aggregates (inclusion) that are possibly neurotoxic. o Inclusions may also inhibit proteolytic degradation, inhibit apoptosis and cause over production of ROS. Huntington’s disease can become more severe in successive generations, and can also begin earlier too – this phenomenon is called anticipation. Inherited prion diseases  Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders affecting livestock, other animals and humans.  Human specific diseases: o Kuru. o Creutzfeldt-Jakob disease. o Gerstmann-Straussler-Scheinker disease. o Fatal familial insomnia. Neuropathological features  There is formation of large sponge-like perforations in the cerebral cortex.    Excessive proliferation of glial cells. Selective loss of neuronal cells. Formation of rod-shaped extracellular amyloid plaques. Creutzfeldt-Jakob disease  Affects about 1 in 1, 000, 000 people/year worldwide (very rare).  About 200 cases per year in USA.  CJD usually appears in later life and runs a rapid course.    Typical symptoms occur ~60 years old, and about 90% of patients die within 1 year. Early symptoms include: o Failing memory. o Behavioural changes. o Lack of coordination. o Visual disturbances. Later symptoms include: o Mental deterioration becomes pronounced. o Involuntary movements. o Blindness. o Weakness of extremities. o Coma may occur. Categories of CJD  Sporadic CJD. o Disease appears even though the person has no known risk factors. o Accounts for at least 85% of cases.  Hereditary CJD. o Family history and/or tests positive for a genetic mutation associated with CJD. o Accounts for about 5 – 10% of cases in the USA.  Acquired CJD. o Transmitted by exposure to brain or nervous system tissue, usually through certain medical procedures. o No evidence that it is contagious through casual contact with a CJD patient. o Less than 1% have been acquired since when it was first described. Causative agent – prion proein (PrP)  Prions are proteinaceous and infectious.  Protein has a stable altered topography.  Can “infect” other proteins by contacting them – more abnormal proteins are produced from normal protein molecules. o Infective PrP = PrPSc (scrapie prion protein). o Normal isoform = PrPC (cellular prion protein).  Abnormal conformation is usually resistant to protein degradation. Genetics  Familial represents 10 – 15% of human spongiform encephalopathies. o CJD = cerebral cortex. o GSS = cerebellum. o FFI = thalamus.  Autosomal dominant inheritance.  All of these diseases are localised to human PrP gene (PRNP) on chromosome 20.  Over 20 different mutations in gene; o 7 cause GSS. o 1 causes FFI. o Remainder cause CJD.  Thought that mutated PRNP gene encodes different PrPSc isoforms that cause specific neurological damage.