Chapter 21. Molecular Mechanisms of Neurological Disease Copyright © 2014 Elsevier Inc. All rights reserved

Figure 21.1 Senile plaques and neurofibrillary tangles are pathological hallmarks of Alzheimer’s disease. Under normal physiological conditions, the amyloid precursor protein (APP) is cleaved by α-secretase to form sAPPα. The remaining fragment of the APP protein may be further cleaved by γ-secretase to form p3. Generation of the sAPPα and p3 fragments does not lead to senile plaque formation. The cytosolic protein, tau, interacts with tubulin to promote microtubule assembly and stability. In Alzheimer’s disease, APP is cleaved by β-secretase to form sAPPβ. The remaining fragment of the APP protein is further cleaved by γ-secretase to form Aβ peptides. These peptides aggregate to form senile plaques, and it is thought that Aβ generation promotes the formation of neurofibrillary tangles by increasing the cellular concentration of reactive oxygen species. This phenomenon leads to activation of kinases that hyperphosphorylate tau. In this state, tau fibrillizes and aggregates into neurofibrillary tangles. Copyright © 2014 Elsevier Inc. All rights reserved

Figure 21.2 Parkinson’s disease may arise from genetic mutations or environmental toxins. About 10% of Parkinson’s disease cases are familial. LRRK2 and PINK1 mutations promote aggregation of α-synuclein and Lewy body formation. Parkin mutations affect the ubiquitination activity of the E3 ligase Parkin, which may affect the degradation and clearance of misfolded α- synuclein from the cell. DJ-1 mutations also lead to development of Parkinson’s disease. Although the exact mechanisms are unclear, it is thought that it increases generation of reactive oxygen species that cause cellular apoptosis. Copyright © 2014 Elsevier Inc. All rights reserved

Figure 21.3 Abnormal prion structure is propagated to normal, endogenous prion forms. In humans, the normal, cellular isoform of the prion protein (PrP C ) can interact with the disease-causing isoform (PrP Sc ). This results in the conversion of PrP C to PrP Sc. PrP Sc accumulates into aggregate deposits, though the nature of its toxicity is not well understood. PrP Sc may be introduced into the system by spontaneous generation or somatic mutation, genetically inherited mutations of PRNP, or by inoculation from an external source of infection. Copyright © 2014 Elsevier Inc. All rights reserved

Figure 21.4 Phenylalanine arises from an enzyme defect of phenylalanine metabolism. Under normal conditions, phenylalanine is converted to tyrosine by phenylalanine hydroxylase (PAH) after consumption of protein. Patients diagnosed with phenylketonuria (PKU) have a defect in PAH, and thus cannot hydroxylate phenylalanine to tyrosine, leading to a buildup of phenylalanine and lack of tyrosine. If left untreated, PKU can lead to severe mental defects, seizures, and mood disorders, among others. Copyright © 2014 Elsevier Inc. All rights reserved

Figure 21.5 Overview of trinucleotide disease mechanisms. Trinucleotide diseases have similar characteristics yet they develop from a variety of pathogenic mechanisms. Fragile X syndrome (FXS), Friedreich’s ataxia, fragile XE intellectual disability, and Jacobsen syndrome arise from genetic loss of function through transcriptional disruption of the mutated gene. Myotonic dystrophy, spinocerebellar ataxia (SCA) 8 and SCA12 occur through defects in RNA processing, allowing for a toxic gain of function (e.g., SCA8, SCA12). Lastly, Huntington’s disease, SCA1, SCA2, SCA3, SCA6, SCA7, and denatorubropalidoluysian atrophy occur from abnormal expression of proteins and/or protein acquisition of toxic properties. Adapted from Nelson et al. (2013). Copyright © 2014 Elsevier Inc. All rights reserved

Figure 21.6 Abnormal expansion of trinucleotides leads to pathogenesis. A. Fragile X syndrome is a genetic syndrome caused by the abnormal expansion of the CGG trinucleotide repeat on the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. This results in loss of the fragile X mental retardation protein (FMRP) and ultimately leads to impaired intellectual ability. B. Huntington’s disease is an inherited autosomal dominant mutation on chromosome 4 that affects the Huntingtin gene (HTT). The HTT mutation leads to an abnormal expansion of the CAG repeat in the HTT gene, leading to abnormal expression of the Huntingtin protein. Huntington’s disease leads to progressive neuronal degeneration. Copyright © 2014 Elsevier Inc. All rights reserved

Figure 21.7 Inherited CMT. There are 27 types of CMT neuropathies caused by mutations in over 50 genes. Demyelinating CMT disorders (CMT1, CMT4) have conduction velocities less than 38 m/s and are caused by genetic mutations in myelin protein zero (MPZ) and the peripheral myelin protein-22 (PMP-22). Axonal CMT disorders (CMT2) have conduction velocities greater than 38 m/s and are caused by genetic mutations in mitofusin-2 (MFN2) and the kinesin family member 1B-beta protein (KI). X-linked CMT disorders (CMTX) have variable conduction velocities and are caused by genetic mutations in connexin-32. All CMT diseases exhibit axonal loss and transport defects, muscle denervation, and sensory losses. Copyright © 2014 Elsevier Inc. All rights reserved

Figure 21.8 Summary of pathogenesis in CNS diseases. A key pathological feature of neurodegenerative diseases is the abnormal aggregation of misfolded proteins. Genetic mutations render the proteins to become structurally unstable and prone to misfold, resulting in their accumulation in neurons. This mechanism is common to a broad spectrum of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and the trinucleotide repeat disorders. Copyright © 2014 Elsevier Inc. All rights reserved