Neurodegenerative Disorders

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Neurodegenerative Disorders

• The Gene-Environment Interaction

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Definition

• Neurodegenerative disease is a condition which
  affects brain function. Neurodegenerative
  diseases result from deterioration of neurons.
  They are divided into two groups
• conditions causing problems with movements
• conditions affecting memory and conditions
  related to dementia.
• Examples
• Alzheimers
• Parkinsons
• Huntingtons
• Creutzfeldt-Jakob disease
• Multiple Sclerosis
• Amyotrophic Lateral Sclerosis (ALS or Lou
  Gehrig's Disease)
• http//www.reference.com/browse/wiki/Neurodegenera
  tive_disease

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Prevalence of Neurodegenerative Diseases

• 4-5 million people in the U.S. with Alzheimers
  disease (AD)
• By 2050 this number is predicted to be 16 million
• 1-1.5 million people in the U.S. with Parkinsons
  Disease
• Thousands with other NDs
• 100,000 deaths/yr attributed to AD

http//ind.medschool.ucsf.edu/
4
Risk Factors

• Known
• Certain genetic polymorphisms
• Increasing age
• Possible
• Gender
• Poor education
• Endocrine conditions
• Oxidative stress
• Inflammation
• Stroke
• Hypertension
• Diabetes
• Head trauma
• Depression
• Infection
• Tumors
• Vitamin deficiencies
• Immune and metabolic conditions

http//www.medscape.com/viewarticle/512458
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Age Risk of Dementia
Percentage of Persons with Moderate to Severe
Memory Impairment
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Protective Factors

• Estrogen
• SIRT1 protein
• Smoking

Colloquium C04 Estrogen and Neurodegenerative
Diseases A Protective Role? 2003 International
Societyfor Neurochemistry, Journal of
Neurochemistry, 85 (Suppl. 1) Study Protein may
slow neurodegenerative disorders September 10
2004 ALS Research
7
Cost of Neurodegenerative Diseases

• Billions of dollars each year
• Direct health care costs
• Lost opportunities
• 100 billion per year Alzheimer disease
• Emotional burden on patients and caregivers
• Number of elderly increasing

http//www.medscape.com/viewarticle/512458
8
Why do some people exposed to an environmental
agents develop disease and others do not?
http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt
9
Alzheimers Brain
Control Brain
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http//www.alzheimersdisease.com/hcp/about/pathoph
ysiology/tau-hypothesis.jsp?usertrack.filter_appli
edtrueNovaId1178761707191819673
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Genetics of Alzheimers

• Genetic Loci of Alzheimer's Disease
• Chromosome 21 (APP) Early Onset FAD
• Chromosome 1 (PS2) Volga German FAD
• Chromosome 14 (PS1) Early Onset FAD
• Chromosome 19 Apolipoprotein (E risk factor)
• http//medir.ohsu.edu/geneview/education/InfoChat
  20Slides.ppt271,4,Brain Atrophy with AD

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http//ibgwww.colorado.edu/carey/p4102dir/slidesd
ir/HGSS_Chapter6_DCG.ppt
13
http//ibgwww.colorado.edu/carey/p4102dir/slidesd
ir/HGSS_Chapter6_DCG.ppt
14
http//ibgwww.colorado.edu/carey/p4102dir/slidesd
ir/HGSS_Chapter6_DCG.ppt http//www.upstate.com/fe
atures/app_lp.asp?c221r556
15
PS1 and PS2 (Presenilin 1 and 2)

• 5 of Alzheimers caused by mutation in these two
  or APP
• Can be inherited in dominant fashion
• Leads to early onset (lt65)

http//www.genetichealth.com/ALZ_Genetics_of_Alzhe
imers_Disease.shtml
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Apolipoprotein E

• ApoE helps carry cholesterol and fat in
  bloodstream
• 3 common forms
• e2, e3, e4
• Apo e4 most linked to leading to Alzheimers (1/3
  of cases?)
• Apo e2 may have protective effect

http//www.dshs.state.tx.us/alzheimers/apolipo.sht
m http//www.merck.com/pubs/mmanual_ha/details/ad2
7_1.html http//www.ncbi.nlm.nih.gov/entrez/query.
fcgi?cmdRetrievedbPubMedlist_uids7847867dopt
Abstract
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Loring, et al. 2001 (Abstract)

• Postmortem analysis of brains of patients with
  Alzheimer's disease (AD) has led to diverse
  theories about the causes of the pathology,
  suggesting that this complex disease involves
  multiple physiological changes. In an effort to
  better understand the variety and integration of
  these changes, we generated a gene expression
  profile for AD brain. Comparing affected and
  unaffected brain regions in nine controls and six
  AD cases, we showed that 118 of the 7050
  sequences on a broadly representative cDNA
  microarray were differentially expressed in the
  amygdala and cingulate cortex, two regions
  affected early in the disease. The identity of
  these genes suggests the most prominent
  upregulated physiological correlates of pathology
  involve chronic inflammation, cell adhesion, cell
  proliferation, and protein synthesis (31
  upregulated genes). Conversely, downregulated
  correlates of pathology involve signal
  transduction, energy metabolism, stress response,
  synaptic vesicle synthesis and function, calcium
  binding, and cytoskeleton (87 downregulated
  genes). The results support several separate
  theories of the causes of AD pathology, as well
  as add to the list of genes associated with AD.
  In addition, approximately 10 genes of unknown
  function were found to correlate with the
  pathology.

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Functional distribution of genes expressed in
Loring et al, 2001
http//medir.ohsu.edu/geneview/education/InfoChat
20Slides.ppt271,4,Brain Atrophy with AD
19
Genetic and Environmental Factors in Alzheimers
Disease
Environment
Genes
Susceptibility Head trauma Vascular
factors HSV-1 Total cholesterol Hypertension
Susceptibility APOE-E ?4
Alzheimers Disease
Probabilistic ?-amyloid precursor Presenilin 1
Presenilin 2
Protective N.S.A.I.D.s Estrogen Education
Slooter Van Duijn, 1997
http//www.offordcentre.com/symposium/Merikangas.p
pt27
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Etiology of Parkinsons Disease

Environmental agents
Genes
Parkinsons disease/parkinsonism
http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt
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Clinical and Epidemiology Studies

• MPTP-induced parkinsonism
• MPP metabolite
• Paraquat

http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt
22
Clinical and Epidemiology Studies

• Occupational exposure to pesticides, metals, and
  PCBs as potential risk factors
• Cigarette smoking
• Compound not identified
• Low MAO B levels
• Caffeine use?

http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt
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Causal Genes

• Analysis of large nuclear families with many
  affected individuals have revealed several single
  gene mutations/locus replications that cause PD
• a-synuclein
• Parkin
• DJ-1
• PINK
• LRRK2

http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt
24
Genes Associated with Sporadic Late Onset
Parkinsons Disease

• Tau H1 haplotype
• a-synuclein promoter variant (SNCA gene)
• Vesicular monoamine transporter-2 (VMAT2)
• UCHL1 variant
• LRRK2

http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt http//www.niehs.nih.gov
/ccpder/emory/proj2.htm http//content.karger.com/
ProdukteDB/produkte.asp?AktionShowPDFProduktNr2
23840Ausgabe230656ArtikelNr82956filename 829
56.pdfsearch22tau20H120Parkinson's22 http//
ghr.nlm.nih.gov/conditionparkinsondisease
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Mechanisms of Rotenone Toxicity
Rotenone
Complex I Inhibition
Oxidative Stress
Betarbet. Neuro Dis, 2006
http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt
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Emerging Genetic Findings in PD Create New
Opportunities

• LRRK2 and environmental exposures
• LRRK2 mutation causes a variable clinical and
  pathological phenotype
• The variable phenotype and the wide range in
  onset age suggest that other genetic variation,
  environmental exposures, and/or stochastic events
  modulate LRRK2-linked disease

Zimprich. Neuron 2004 44601 Taylor. Science,
2006
http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt
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Figure 1. Pedigree Structure of the Two Largest
Kindreds with LRRK2 Mutations Shown are family A
(German-Canadian) and family D (Western
Nebraska). Blackened symbols denote affected
family members. An asterisk denotes a genotyped
individual, with m for mutation carriers and
wt for wild-type LRRK2. To maintain
confidentiality, genotypes of some unaffected
individuals in families A and D are not shown.
Additionally, the structure of the pedigrees has
been altered, and the genders of individuals in
some of the youngest generations have been
disguised.
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http//www.sciencedirect.com.ezproxy.fiu.edu/scien
ce?_obArticleURL_udiB6WSS-4DTJSCW-8_coverDate
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54271_version1_urlVersion0_userid2139759md5
91779098222ada73a03a46495c788041
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http//www.sciencedirect.com.ezproxy.fiu.edu/scien
ce?_obArticleURL_udiB6WSS-4DTJSCW-8_coverDate
112F182F2004_alid465464678_rdoc1_fmt_orig
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Environmental Exposures Can Simplify Complex
Diseases
Environmental Exposures
LRRK2 Gene
Phenotype/Pathology

PCBs, infections
http//www.niehs.nih.gov/od/presentations/ppt/NIH-
DHHS/PD-Schwartz-2006.ppt
31
Ethical, Social, Legal issues Neurodegenerative
Diseases

• No guidelines
• Issues
• Informed consent
• Confirmatory testing
• Predictive testing
• Asymptomatic testing for children confidentiality
  
• Insurability
• Employment
• Disability
• Marriage

http//www.bioethics-singapore.org/resources/pdf/A
nnex20C-520Dr20Tan20Eng20King.pdfsearch22n
eurodegenerative20disease20gene20legal20issues
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