Lecture-25-2011-Bi-CNS150

Lecture-25-2011-Bi-CNS150 - Bi / CNS 150 Lecture 25 Monday...

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1 Bi / CNS 150 Lecture 25 Monday November 21, 2011 Two neurodegenerative diseases Henry Lester Kandel, Chapters 43 & 58
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2 James Parkinson, apothecary surgeon 1817, An Essay on the Shaking Palsy , described "paralysis agitans", from observations of 6 individuals during his daily walks in London Parkinson’s disease (tremor at rest 3-5 Hz, “pill-rolling”, slow movements, particularly when starting; short, rapid steps) but most Parkinson patients are either medicated or stimulated Parkinson’s disease 1. Clinical description 2. Genetics 3. Pathophysiology 4. Biomarkers and animal models 5. Heterozygote advantage: none known 6. Therapeutic approaches
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Rodent brain section, stained for tyrosine hydroxylase: coronal view 3 Dopaminergic neurons in the human brain: Saggital view Substantia Nigra: Dopaminergic neurons die in PD Ventral tegmental area: Dopaminergic neurons remain healthy
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4 Only dopaminergic neurons express the cell membrane dopamine transporter. Antidepressants (“SSRIs” = serotonin- selective reuptake inhibitors): Prozac Zoloft Paxil Drugs of abuse: MDMA Attention-deficit disorder medications: Ritalin Dexedrine Drugs of abuse: Cocaine Amphetamine like several previous Lectures Na + -coupled cell membrane serotonin transporter Na + -coupled cell membrane dopamine transporter N H HO NH 3 + HO HO H 2 C C H 2 NH 3 + cytosol synaptic cleft
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5 1. Most cases are unexplained 2. The “frozen addict”. An impurity in synthetic heroin. Taken up by the dopamine transporter (expressed only in dopaminergic cells). Kills cells. 3. The influenza pandemic (worldwide epidemic) of 1918, killed 20 million people. The flu specifically killed dopaminergic neurons in many people (“Awakenings”). 4. Genetics: see next topic 5. Smoking protects against PD. HO HO H 2 C C H 2 NH 3 + dopamine reactive: oxidative damage? Parkinsonism in people
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6 3. Genetics. Familial Parkinson’s Disease Provides a Good Review of Bi 8/9 (~ 10% of patients). Onset 30’s to 50’s (rarely earlier or later) Locus Chromosome location Gene or protein name Inheritance pattern PARK1 & PARK4 4q21–q23 α -synuclein (Unknown function) AD PARK2 6q25.2-q27 Parkin E3 Ubiquitin ligase AR PARK3 2p13 Unknown AD, IP PARK5 4p14 UCH-L1 ubiquitin-C-terminal hydrolase-L1 AD PARK6 1p35-p36 PINK1, PTEN-Induced Putative Kinase 1 AR PARK7 1p36 DJ-1 AR PARK8 12cen LRRK2 leucine-rich repeat kinase 2 AD PARK9 1p36 ATP13A2 AD PARK10- PARK16 Various Much less is known various AD, autosomal dominant; AR, autosomal recessive; IP, incomplete penetrance
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7 α -synuclein has an unknown function; it’s an “intrinsically disordered protein”. Mutant
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This note was uploaded on 01/03/2012 for the course BI 150 taught by Professor Kennedy,m during the Fall '08 term at Caltech.

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Lecture-25-2011-Bi-CNS150 - Bi / CNS 150 Lecture 25 Monday...

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