Great question. I hope you are buckled in, because I've got some big ugly words to throw your way! here is the VERY technical answer to your question:
The symptoms of Parkinson's disease result from the greatly reduced activity of pigmented dopamine-secreting (dopaminergic) cells in the pars compacta region of the substantia nigra (literally "black substance"). These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement. In essence, GABA/ Substance P of the direct pathways diminish, leading to less inhibition of the pars reticulata and internal globus palidus and an inhibition of the indirect pathway by way of GABA/ enkaphalins.
Black-staining granules of neuromelanin within neurons of the substantia nigra
The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack of dopamine results in increased inhibition of the ventral anterior nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.
There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.
The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteasome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies. The latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles - the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.
Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions. Iron and other transition metals such as copper bind to neuromelanin in the affected neurons of the substantia nigra. Neuromelanin may be acting as a protective agent. The most likely mechanism is generation of reactive oxygen species. Iron also induces aggregation of synuclein by oxidative mechanisms. Similarly, dopamine and the byproducts of dopamine production enhance alpha-synuclein aggregation. The precise mechanism whereby such aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. Based on this mechanistic hypothesis, a transgenic mouse model of Parkinson's has been generated by introduction of human wild-type alpha-synuclein into the mouse genome under control of the platelet-derived-growth factor-β promoter.
A recent view of Parkinson's disease implicates specialized calcium channels that allow substantia nigra neurons, but not most neurons, to repetitively fire in a "pacemaker" like pattern. The consequent flooding of calcium into these neurons may aggravate damage to mitochondria and may cause cell death. One study has found that, in experimental animals, treatment with a calcium channel blocker isradapine had a substantial protective effect against the development of Parkinson's disease.
If you are satisfied with the response, please hit "Accept." That is the only way i can receive credit for my answer. Thanks!
I would also like to know some behavioral changes that occur with PD.
No problem! Here you go... good luck on your assignment!
Four motor symptoms are considered cardinal in PD: tremor, rigidity, bradykinesia and postural instability. Tremor is the most apparent and well-known symptom. It is most commonly a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep. It affects to a greater extent the most distal part of the extremity and is typically unilateral at onset. Though around 30% of PD sufferers do not have tremor at disease onset most of them would develop it along the course of the disease. Rigidity is due to joint stiffness and increased muscle tone, which combined with a resting tremor produce a ratchety, "cogwheel rigidity" when the limb is passively moved. Rigidity may be associated with joint pain, such pain being a frequent initial manifestation of the disease. Bradykinesia (slowness of movement) is the most characteristic clinical feature of PD and it produces difficulties not only with the execution of a movement but also with its planning and initiation. The performance of sequential and simultaneous movements is also hindered. In the late stages of the disease postural instability is typical, which leads to impaired balance and falls.
PD motor symptomatology is not limited to these four symptoms. Gait and posture disturbances such as decreased arm swing, a forward-flexed posture and the use of small steps when walking; speech and swallowing disturbances; and other symptoms such as a mask-like face expression or a small handwriting are only examples of the ample range of common motor problems that can appear with the disease.
Parkinson's disease causes neuropsychiatric disturbances, which include mainly cognition, mood and behavior problems and can be as disabling as motor symptoms.
Cognitive disturbances occur even in the initial stages of the disease in some cases. A very high proportion of sufferers will have mild cognitive impairment as the disease advances. Most common cognitive deficits in non-demented patients are executive dysfunction, which translates into impaired set shifting, poor problem solving, and fluctuations in attention among other difficulties; Slowed cognitive speed, memory problems; specifically in recalling learned information, with an important improvement with cues; and visuospatial skills difficulties, which are seen when the person with PD is for example asked to perform tests of facial recognition and perception of line orientation.
Deficits tend to aggravate with time, developing in many cases into dementia. A person with PD has a sixfold increased risk of suffering it, and the overall rate in people with the disease is around 30%. Moreover, prevalence of dementia increases in relation to disease duration, going up to 80%. Dementia has been associated with a reduced quality of life in disease sufferers and caregivers, increased mortality and a higher probability of attending a nursing home.
Cognitive problems and dementia are usually accompanied by behavior and mood alterations, although these kind of changes are also more common in those patients without cognitive impairment than in the general population. Most frequent mood difficulties include depression, apathy and anxiety. Obsessive-compulsive behaviors such as craving, binge eating, hypersexuality, pathological gambling, or other, can also appear in PD, and have been related to a dopamine dysregulation syndrome associated with the medications for the disease.
In addition to cognitive and motor symptoms PD can impair other body functions. Sleep problems can be worsened by medications for PD, but they are a core feature of the disease. They can manifest as excessive daytime somnolence, disturbances in REM sleep or insomnia. The autonomic system is altered which can lead for example to orthostatic hypotension, oily skin and seborrheic dermatitis, excessive sweating, urinary incontinence and altered sexual function. Constipation and gastric dysmotility can be severe enough to endanger comfort and health. PD is also related to different ophthalmological abnormalities such as decreased blink rate and alteration in the tear film, leading to irritation of the eye surface, abnormalities in ocular pursuit and saccadic movements and limitations in the upward gaze. Changes in perception include reduced sense of smell and sensation of pain and paresthesias.
If you are satisfied with the response, please hit "Accept." That is the only way I can receive credit for my answer. Thanks-