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Parkinson’s disease and Huntington’s disease are regarded primarily as
diseases of the basal ganglia
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The term basal ganglia refers to a system of interconnected subcortical nuclei responsible
for guiding intention into action and further sequencing motor programs into a smooth
response
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This can be exemplified through pathology of the basal ganglia producing
symptoms such as dyskinesia, tremor and choreoathetosis
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Experiments carried out predominantly in animal models have
allowed for the development of a direct vs indirect pathway model
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Furthermore
understanding of the interactions between the basal ganglia has allowed for the
development of successful treatment for the disease processes aforementioned
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It wasn’t until subthalamectomy experiments were conducted on monkeys by
DeLong et al in 1990 that the basal ganglia were associated with a dopamine deficiency
induced inhibitory stimulus driving the akinesia of Parkinsonism
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Not only did this demonstrate the necessity for basal
ganglia function in movement control but also hinted at the neural pathways acting within,
in both health and disease
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As seen in the figure below drive for motion generated in the cortex projects directly to the
striatum – with the striatum being formed by the putamen and cordate nucleus
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In inhibiting the substantia nigra reticularis and globus
pallidus interna; the striatum blocks their inhibitory action on the thalamus
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Simultaneously the striatum also inhibits the
globus pallidus externa; thus blocking the globus pallidus externa’s inhibitory action on the
subthalamic nucleus
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The neuroanatomy therefore allows for the induction of two directly opposing processes in
response to higher cortical stimulation
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Dopamine released from the substantia nigra compacta in the midbrain
indiscriminately binds both D1 and D2 receptors
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Whilst D1 receptors depolarise neurons, making an action potential more likely; D2
receptors promote hyperpolarisation and therefore neuron inactivity
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Alternatively in times of low dopamine concentration the indirect
pathway prevails and the intention to move provided by the cortex is suppressed
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In inducing
Parkinsonian symptoms through dopaminergic neuron destruction (MPTP); DeLong et al’s
experiment therefore provides conclusive evidence for both the arrangement of inhibitory
and stimulatory neurons, but also the asymmetric distribution of dopamine receptors
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As can be
appreciated in the diagram below subthalamectomy permanently removes the inhibitory
action of the indirect
pathway; leaving
permanent direct
pathway processes
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Firstly the role of dopamine in determining the ratio of direct:indirect
pathway action is confirmed by the efficacy of L-DOPA (a dopamine precursor) as a
treatment for Parkinson’s
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Therefore it is becoming increasingly common to instead conduct
deep brain stimulation (DBS) whereby electrodes are embedded in the subthalamic nucleus
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Unlike in DeLong’s experiment, dopaminergic neuron death is (hopefully) not induced by
MPTP in humans
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I believe it could be possible that dopaminergic neurons are
inherently more susceptible to trauma than other neurons – hence Parkinsonism presents
commonly in retired boxers and rugby players - although this could be simply the result of
dopaminergic neurons being fewer in number than other neurons
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Thereby rendering dopaminergic neurons more susceptible to apoptosis as the
result of elevated intracellular calcium concentrations
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The
concept of excessive direct
pathway drive in
Huntington’s came from
pharmacological
experiments conducted in
non-Huntington’s patients but still those experiencing choreoathetosis
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The exact mechanism for increased direct pathway flux remained unknown until 2007 (Tang
et al)
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This renders the globus
pallidus externa’s inhibitory action on the subthalamic nucleus irreversible
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Tang et al proved a dopamine dominant
mechanism through the efficacy, of what is now a front line routine treatment, of the
dopamine secretion antagonist tetrabenazine
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Tetrabenzine
therefore reduces the availability of dopamine within the basal ganglia system – reducing

direct pathway drive
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Huntington’s patients therefore will
always have a tendency to persist in erratic movement
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Although this very precise genetic determinant has been
discovered, the molecular pathophysiology of Huntington’s has yet to be elucidated
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Ahmed et al (2015) showed a strong negative
correlation between the Huntington gene and inositol polyphosphate multikinase (IPMK)
concentration in cell culture
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Therefore Ahmed was unable to describe
causality, only correlation, and the molecular mechanisms of Huntington’s remain
anonymous
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Although many details have yet to be discovered, methods of treatment and
clinical presentations appear to fit the basal ganglia model
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By further understanding the molecular mechanisms (and possible
further sub types of dopaminergic neurons) there is the hope that curative treatment could
be produced for Huntington and Parkinson patients, rather than simply palliative care
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2016
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s
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: Wolters Kluwer, 2016
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Tang et al
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2007
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Standring et al
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s
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: Elsevier, 2016
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Ahmed et al
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2015
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2012
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s
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: Mc Graw Hill, 2012
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DeLong et al
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1990
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Albin et al
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1989
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2010
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Wilkins
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Oxford handbook of medical sciences (2nd Edition)
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Young et al
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Basic Clincial Neuroscience
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l
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