Neurodegenerative Disease April 12, 2017 Cunningham Department of Neurosciences
NEURODEGENERATIVE DISEASE Any of a group of hereditary and sporadic conditions characterized by progressive dysfunction, degeneration and death of specific populations of neurons which are often synaptically interconnected. Some of the more common or well-known neurodegenerative diseases are: 1. Alzheimer s Disease (most common) 2. Parkinson s Disease 3. Amyotrophic Lateral Sclerosis 4. Huntington s disease Others: Progressive supranuclear palsy, multisystem atrophy, Spinocerebellar ataxias, spinal muscular atrophy, frontotemporal degeneration, Suggested Reading: Walker and Jucker (2015) Neurodegenerative Diseases: Expanding the Prion Concept Annual Review of Neuroscience Neuroscience 38:87-103.
NEURODEGENERATIVE DISEASE Pathogenesis & Therapeutic Approaches 1. Parkinson s Disease (movement control) Hypokinetic Movement Disorder 2. Huntington s Disease (movement control) Hyperkinetic Movement Disorder 4. Alzheimer s Disease (cognition) Cognitive Impairment, Memory Loss These neurodegenerative diseases target distinct neuronal circuits in the CNS
BASAL GANGLIA A SET OF LARGE NUCLEI DEEP WITHIN THE BRAIN (Caudate Nucleus, Putamen, Globus Pallidus)
The Substantia Nigra is a region in the brainstem that provides dopaminergic innervation to the basal ganglia via the nigrostriatal pathway. The nigrostriatal pathway degenerates in Parkinson s disease.
The basal ganglia are comprised of the Caudate, Putamen and Globus Pallidus. The Subthalamic Nucleus And Substantia nigra Are Involved in motor function of basal ganglia
PARKINSON S GAIT http://www.youtube.com/watch?v=j86omowx0hk https://www.youtube.com/watch?v=sf1n0zf5iqa
Cardinal Signs of Parkinson s Disease Resting Tremor Posture Instability Rigidity with Cogwheeling Bradykinesia Difficulty rising Micrographia
Parkinson s Disease (Basal Ganglia Movement Disorder) 1817 1960 s DA hypothesis 2015 Protein Misfolding
Programming Execution Basal Ganglia Associative Cortex SMA - Thalamus VA + VL Globus Padillus + Primary + Premotor Cortex Red Nucleus Corticospinal Rubrospinal Pons + Deep Cerebellar Nuclei Reticular Nuclei Reticulospinals Cerebellum Vestibular Complex Vestibulospinal
Basal Ganglia Parallel Processing Loops regulate both Motor and Non-Motor Function
PARKINSON S DISEASE 1. Progressive Neurodegenerative Disease involving degeneration of the nigrostriatal dopaminergic neurons 2. Second most common neurodegenerative disorder 3. Mean Age of Onset - 55 yrs. 4. Incidence Increasese with Age: 20/100,000 vs. 120/100,000 (70 yrs) 5. Sporadic PD 95% of PD cases 6. Inherited PD -synuclein, parkin, ubiquitin hydrolase 7. Effective pharmacological treatment available, but no cure
Primary PARKINSON s SYNDROMES Secondary Parkinson-plus PD Usually Requires Clinical Diagnosis
Pathological Hallmarks of PD 1. Loss of Dopaminergic Neurons in the Substantia Nigra. 2. Appearance of Lewy body neuronal cytoplasmic inclusions
Symptoms occur after 80% loss of nigral neurons Why? Compensatory Mechanisms 1. Increased DA production 2. Increased DA Receptor expression 3. Collateral Sprouting
PD Pathogenesis 95% of all cases are sporadic and of unknown etiology Possible Causative Factors: -mitochondrial dysfunction -oxidative stress -excitotoxins -deficient neurotrophic factor support -immune mechanisms -aberrent proteosome function Genetic Susceptibility and Environmental Exposures
1. Metabolism MPTP TOXICITY IN DA NEURONS 3. Inhibition of Oxidative Phosphorylation 2. Uptake by DA Neurons Structural Similarities between MPTP and Pesticides
Preclinical Toxin Models of PD Advantages: 1. Understand mechanisms of environmental toxicities Environmental health 2. Preclinical model for testing dopamine replacement strategies Pharmacological Replacement of Dopamine Cellular Replacement of Dopaminergic Neurons through transplantation 3. Dysregulation of basal ganglia circuitry and role of dopamine in modulation of basal ganglia function Disadvantages: 1. Poor model of the disease process (not progressive) 2. Does not recapitulate the natural course of disease, nor all pathological hallmarks
Pharmacotherapy for Parkinson s Disease L-DOPA/Carbidopa (Sinemet) COMT INHIBITORS (Entacapone) MONOAMINE OXIDASE INHIBITORS (Selegiline) DOPAMINE RECEPTOR AGONISTS (Ropinerole, Pramipexole) ANTICHOLINERGICS (Benztropine)
DOPAMINERGIC TERMINAL
Carbidopa greatly enhances the bioavailability of L-dopa to CNS DopaDecarboxylase CARBIDOPA L-dopa DOPAMINE LNAA Transporter L-dopa DOPAMINE DDC
L-DOPA DOSING LEADS TO PULSTILE DOPAMINE RECEPTOR IN PATIENTS WITH ADVANCED PARKINSON s DISEASE due to loss of buffering capacity as nigral neurons degenerate PULSATILE RECEPTOR STIMULATION Postsynaptic Gene Expression Changes L-DOPA MEDIATED DYSKINESIAS
IN VITRO IN VIVO
Designer Receptors Exclusively Activated by Designer Drugs = DREADDs Chemogenetics for Remote Control of Graft Function
Use of Chemogenetic Technology to Test Graft Function using DREADS Clozapine N Oxide http://www.sciencedirect.com/science/article/pii/s1934590916300017
DEEP BRAIN STIMULATION DBS
Loss of Dopamine in Basal Ganglia Circuitry Disrupting the balance of inhibitory signals in the direct and indirect pathways leading to tonic inhibition of thalamocortical input to frontal cortex
D2- D1+
Pallidotomy -Improved l-dopa-induced dyskinesia (80% or more). -Unilateral pallidotomy results in contralateral, often transient improvements. -Risk of adverse effects with bilateral pallidotomy.
Bilateral Deep-Brain Stimulation of The Globus Pallidus or Subthalamic Nucleus -Inhibits neuronal activity. -Reversible
https://www.youtube.com/watch?v=t3 QQOQAILZw
FAMILIAL (Inherited) PD LOCUS GENE Type of Mutation Inheritance PARK1 -synuclein PM, Dupl, Tripl AD PARK 2 Parkin PM,Dupl, Trpl, Ins, Del AR PARK 5 UCH-L1 PM AD PARK 6 PINK1 PM, Ins, Del AR PARK 7 DJ1 PM, Del AR PARK 8 LRRK2 PM,Del AD PARK9 ATP13A2 PM, Del AR PARK13 Omi/HtrA2 PM, AD
Pathological Hallmarks of PD 1. Loss of Dopaminergic Neurons in the Substantia Nigra. 2. Appearance of Lewy body neuronal cytoplasmic inclusions
1. Genetic Models Insight into PD etiology