This slide deck covers the neurobiology and aetiology of Parkinson’s Disease (PD). Pathogenetic details, including underlying common pathways and treatment designs based on the pathogenesis model, are discussed. In addition, α-synuclein and the prion hypothesis of PD are briefly reviewed.

This slide deck has been developed in collaboration with the former Lundbeck International Neuroscience Foundation.

Index for
slide deck

Title

Neurobiology and aetiology
Neurobiology and aetiology

This presentation covers aetiology of Parkinson’s disease.

file_download Download slide in HQ

Neurobiology

Neurobiology
Neurobiology
file_download Download slide in HQ
The motor cortex
The motor cortex

Motor activity is controlled by projections that range from the primary motor cortex and the premotor cortical areas of the frontal lobe through to the brainstem and spinal cord.[Patestas & Gartner, 2016] The primary motor cortex has an important function in the execution…

file_download Download slide in HQ
The basal ganglia
The basal ganglia

Normal motor function is the result of complex and intricate interactions between the basal ganglia, the cerebellum, and the cerebral cortex.[Patestas & Gartner, 2016] The main function of the basal ganglia is to initiate motor activity and to control cortical outputs – i…

file_download Download slide in HQ
The direct and indirect motor pathways
The direct and indirect motor pathways

Direct motor pathway mechanism (facilitates movement)
The direct motor pathway goes from the striatum to the globus pallidus interna (GPi) via fibres that inhibit GPi activity.[DeLong, 2000] When this occurs, the GPi no longer inhibits the thalamus, which is now able to s…

file_download Download slide in HQ
Neurotransmitters and the presynaptic and postsynaptic neurons
Neurotransmitters and the presynaptic and postsynaptic neurons

Cells of the nervous system communicate with each other at synapses, either via electrical signals or by the release of messenger molecules called neurotransmitters.[Patestas & Gartner, 2016] Examples of neurotransmitters include: acetylcholine, adrenaline, dopamine, sero…

file_download Download slide in HQ
The role of dopamine in the brain
The role of dopamine in the brain

Dopamine is an excitatory neurotransmitter present in the neurons of several regions of the central nervous system.[Patestas & Gartner, 2016] The major dopamine-containing area is the corpus striatum, which plays a central role in the coordination of body movements.[Pates…

file_download Download slide in HQ

The pathogenesis of Parkinson’s disease

The pathogenesis of Parkinson’s disease
The pathogenesis of Parkinson’s disease
file_download Download slide in HQ
Lewy bodies
Lewy bodies

A Lewy body is largely composed of misfolded, insoluble α‑synuclein.[Halliday et al., 2014] There are, however, many other components of Lewy bodies, including structural fibril proteins, α‑synuclein-binding proteins, and cellular components normally involved in the degra…

file_download Download slide in HQ
α-synuclein
α-synuclein

The protein α-synuclein was first isolated from human brain tissue during the early 1990s.[Burré, 2015] Its role in PD only became apparent in 1997, when a mutation in the α-synuclein gene was discovered in groups affected by a rare, autosomal-dominant form of familial pa…

file_download Download slide in HQ
Dopaminergic cell loss in Parkinson’s disease
Dopaminergic cell loss in Parkinson’s disease

The overall level of atrophy of brain tissue does not seem to differ between patients with PD and age-matched controls.[Halliday et al., 2014]
However, by the time a patient with PD develops motor symptoms, they will have suffered a moderate-to-severe loss of neuromelanin…

file_download Download slide in HQ
Braak staging of Parkinson’s disease
Braak staging of Parkinson’s disease

At a physiological level, PD is characterised by the loss of neurons in specific regions of the brain and a spreading of Lewy pathology.[Halliday et al., 2014] However, these do not necessarily always go together; many regions with a concentration of Lewy pathology show o…

file_download Download slide in HQ
Distribution of α-synuclein pathology in Parkinson’s disease
Distribution of α-synuclein pathology in Parkinson’s disease

The Lewy pathology and aggregated α-synuclein proteins associated with PD are not confined to the central nervous system (CNS); they can also be found in the peripheral nervous system at various sites around the body, such as the skin, gastrointestinal tract, and salivary…

file_download Download slide in HQ
The gastrointestinal system and Parkinson’s disease
The gastrointestinal system and Parkinson’s disease

Neurons found in the enteric (gut) nervous system (ENS) require dopamine.[Rao & Gershon, 2016] Without dopamine, these neurons cannot properly control gastrointestinal motility.[Rao & Gershon, 2016] Animal studies have suggested that the ENS may be vulnerable to degenerat…

file_download Download slide in HQ

Related content

image Image
Trajectories of neurodegeneration in body- and brain-first subtypes of Lewy body disease

In brain-first patients (bottom panel), the dopamine system starts to degenerate early

23.01.2025 Parkinson’s Disease
image Image Characteristics of proposed body-first and brain-first subtypes of PD. Arrows indicate the direction of spread of α-synuclein pathology. In body-first Parkinson disease (left), the first α-synuclein aggregation occurs in the gut and propagates through the sympathetic nervous system to the sympathetic trunk and heart, and via the vagus nerve to the brainstem. Autonomic dysfunction and REM sleep behaviour disorder (RBD) are prodromal features. In brain-first PD (right), the initial α-synuclein pathology enters via the olfactory bulb (OB) and spreads to the amygdala and nigrostriatal dopamine system. The pathology then descends through the brainstem and RBD and dysautonomia generally develop after the onset of parkinsonism. During the later disease stages, nearly all patients have widespread pathology in these systems and their symptomatology therefore converges.
Body-first vs brain-first Lewy Body Disease

Characteristics of proposed body-first and brain-first subtypes of Parkinson’s disease

23.01.2025 Parkinson’s Disease
image Image
The Trajectory of Brain-first and Body-first PD

The body-first and brain-first model suggests that the clinical subtype with mild or no “bodily symptoms” before diagnosis reflects a brain-first origin of the disease

23.01.2025 Parkinson’s Disease