Cytosolic non-vesicular dopamine accumulation as the predominant mechanism for developing non-DOPA responsive parkinsonism in late-stage Huntington disease.

Cytosolic non-vesicular dopamine accumulation as the predominant mechanism for developing non-DOPA responsive parkinsonism in late-stage Huntington disease.

Publication date: Nov 01, 2019

Disturbances in motor movement can have similar clinical presentations, albeit having different pathways and temporal onset. Hypokinetic movements present with rigidity, resting tremors, postural instability and bradykinesia, as seen in parkinsonism, while hyperkinetic movements typically present with chorea, ballismus, tic, athetosis and dystonia. Nonetheless, movement disorders are thought to be a continuum. Long-term therapy of parkinsonism with L-DOPA or dopamine (DA) agonists leads to late-onset dyskinesia – a hyperkinetic movement disorder, while patients with late-stage Huntington disease (HD) often develop non-DOPA responsive parkinsonism. In this paper, it is proposed that late-onset parkinsonism is driven by the overactivity of the nigrostriatal dopaminergic pathway. The excessive synthesis, storage, release, reuptake and degradation of dopamine in the presynaptic terminal and synaptic clefts lead to cellular stress and damage, resulting to progressive neuroapoptosis aggravated by pro-parkinsonism drugs used to treat hyperkinesia. Glutamate excitotoxicity may provide initial stress to neurons during early HD – but as the disease advances, lower glutamate levels are observed, making it less likely to cause the hypokinetic shift on its own. Over time, dopaminergic neurons are depleted and cholinergic influence to striatal GABA release is unopposed, leading to late-onset parkinsonism that is unresponsive to DOPA challenge, due to drastic DA neuron loss previously masked by the dominating choreic presentation. This paper thus provides a mechanism of action to a common clinical sequela and complication of long-term choreic diseases, whose pathophysiologic mechanism is presently lacking.

Manalo, R.V.M. Cytosolic non-vesicular dopamine accumulation as the predominant mechanism for developing non-DOPA responsive parkinsonism in late-stage Huntington disease. 06743. 2019 Med Hypotheses (132):

Concepts Keywords
Athetosis Parkinson’s disease
Bradykinesia Catecholamines
Cholinergic Neurological disorders
Chorea Nervous system
DA Organ systems
DOPA Late onset parkinsonism
Dopamine Onset parkinsonism
Dopaminergic Diseases
Dopaminergic Pathway Pro parkinsonism
Dyskinesia Movement disorders
Dystonia Hypokinesia
Excitotoxicity Hyperkinesia
GABA L-DOPA
Glutamate Movement disorders
Huntington Nigrostriatal pathway
Movement Disorder Substantia nigra
Movement Disorders Chorea
Neuron
Neurons
Nigrostriatal
Parkinsonism
Pathophysiologic
Postural Instability
Presynaptic Terminal
Progressive
Reuptake
Sequela
Stress
Striatal
Synaptic
Tic
Vesicular

Semantics

Type Source Name
gene UNIPROT PSD4
disease MESH tic
disease MESH ballismus
disease DOID chorea
disease MESH chorea
disease MESH hyperkinetic movements
disease MESH bradykinesia
disease MESH resting tremors
disease DOID Huntington disease
disease MESH Huntington disease
drug DRUGBANK Dopamine
drug DRUGBANK gamma-Aminobutyric acid
gene UNIPROT MAGEE1
pathway BSID Release
drug DRUGBANK Levodopa
disease MESH movement disorders
disease DOID dystonia

Similar

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *