Pathophysiology of Parkinson's Disease

       In general, it can be said that Parkinson's disease occurs as a result of decreased levels of dopamine neuron death in the substantia nigra pars compact by 40 - 50% were accompanied by eosinophilic cytoplasmic inclusions (Lewy bodies). Lewy bodies are eosinophilic cytoplasmic inclusions with concentric peripheral halo and dense cores .

Presence of Lewy bodies in the neurons of the substantia nigra pigment is typical, but not pathognomonic for Parkinson's disease, as there is also in some cases of atypical parkinsonism. To better understand the pathophysiology that occurs must be known beforehand about the basal ganglia and the extrapyramidal system.

1. Basal ganglia
       In running, motor function, spinal cord motor nucleus under the control of motor cortical pyramid cells, directly or through the core of the brain stem. Direct control by the motor cortex via pyramidal tract, whereas, the indirect through the extrapyramidal system, in which the basal ganglia play a role. Complementation pyramidal tract working with extrapyramidal system causing muscle movement becomes smooth, purposeful and programmed.
Basal ganglia (BG) is composed of some of the core group, namely:
1. Striatum (neostriatum and limbic striatum)
    Neostriatum consists of the putamen (Put) and caudate nucleus (NC)
2. Globus Palidus (GP)
3. Substantia Nigra (SN)
4. Subthalamic Nucleus (STN)
       BG influence to muscles  movement, it can be shown through participation in BG motor circuit is established between the motor cortex to the spinal cord core. There afferent nerve pathways from the motor cortex, premotor cortex and supplementary area motorcycle heading to BG through the putamen. From the putamen forwarded to GPI (Globus Palidus internus) via the direct (direct) and indirect (indirect) through the GPE (Globus Palidus externus) and STN. Of GPE forwarded towards the core - the core of the thalamus (among others: VLO: Ventralis lateralis pars oralis, VAPC: Ventralis parvocellularis pars anterior and CM: centromedian). Then headed to the cortex where the path originated tersebur. Input from BG motor circuit is then affect corticospinalis (pyramidal tract).
       The core group is incorporated in the basal ganglia are related to each other through different neural pathways - different materials instrumentality (neurotransmitter / NT).
There are three main types of neurotransmitters in the basal ganglia, which are: Dopamine (DA), acetylcholin (Ach) and amino acids (glutamate and GABA)

2. Pathophysiology of Basal Ganglia
       A little hard to understand the mechanisms underlying abnormalities in the basal ganglia because of the relationship between the group - a core group there are very complex and nerves connecting using a variety of neurotransmitters. However, there are two rules that need to be considered in order to understand its role in the pathophysiology of basal ganglia disorders.
1. The functional units are innervated  by more than one nervous system, so  it is reciprocal innervation inhibition (reciprocal of the debilitating neurological component to another component). This means that one acts as the excitation and the other as the inhibition of the function. The classic example is the function of reciprocal inhibition between nerve sympathetic autonomic nerves to NT noradrenaline (NA) and the parasympathetic nervous with NT acetylcholine (Ach).
2. The unit functions normally when the activities of neural excitation equal or balanced by neural inhibition. When by various diseases or medications change the balance of these symptoms or hypokinesia hiperkinesia dependent neuronal excitation or inhibition of components that excessive activity.\

       Pathophysiology BG explained through two approaches, based on how the drugs cause changes in dopaminergic nerve balance with cholinergic nerves, and changes in the balance of directors pathway (inhibition) and indirect pathways (excitation).

       Primary lesion in Parkinson's disease is a degeneration of nerve cells, which contain neuromelanin in the brain stem, particularly in the substantia nigra pars compact, which becomes pale. Normal conditions (physiological), the release of dopamine from nerve endings nigrostriatum will stimulate D1 receptors (excitatory) and D2 receptors (inhibitory) located in, the output neuron dendrites striatum. Output striatum channeled to the internal segment of the globus palidus or substantia nigra pars reticularis through two channels, namely D1 receptor pathways director and indirect pathways associated with D2 receptor. So when the direct and indirect input balanced, then there is no movement abnormalities.

       In patients with Parkinson's disease, there is degeneration of the substantia nigra pars compact damage and dopaminergic nerve nigrostriatum so there is no stimulation of D1 and D2 receptors. Symptoms of Parkinson's disease has not yet appeared, until more than 50% damaged dopaminergic neurons and dopamine were reduced by 80%. D1 receptors (excitatory) are not aroused, so the track director with neurotransmitter GABA (inhibitory) is not activated. Receptor D2 (inhibitory) are not aroused, so that indirect pathway from the putamen to the external segment of the globus palidus GABAergik nothing that inhibits the function of inhibitory against excessive external segment of the globus palidus. Inhibition of neuronal function GABAergic segment of the globus palidus eksterna to weaken subthalamic nucleus and nucleus neuron activity subthalamic increased due to inhibition.

       There is  increasing output subthalamic nucleus to the internal segment of the globus palidus / substantia nigra pars reticularis through glutaminergic nerves that are excitatory neurons resulting in increased activity globus palidus / substantia nigra. This situation is intensified by the lack of inhibitory function of the direct path, so that the basal ganglia output becomes redundant towards the thalamus.

       Efferent nerves of the internal segment of the globus palidus to the thalamus is GABAnergic so thalamus activity will be depressed and the subsequent stimulation of the thalamus to the cortex via neural glutamatergic output will decrease and the motor cortex to the spinal cord motor neurons are weakened, there hypokinesia.

Biomolecular studies of Parkinson's disease
      Postmortem studies have consistently highlighted the presence of oxidative damage in the pathogenesis of PD, and in particular oxidative damage to lipids, proteins, and DNA can be observed in the substantia nigra pars compact (SNC) PD patients' brains, sporadic. Oxidative stress would harm the integrity of the neuron so as to accelerate the degeneration of neurons. Source of increased oxidative stress is still unclear, but may involve mitochondrial dysfunction, increased metabolism of dopamine produces hydrogen peroxide and reactive oxygen species (ROS) rest in large quantities, increased reactive iron, and impaired antioxidant defense pathways.

    Selective decrease by 30-40% in the complex-I activity of mitochondrial respiratory chain was found in patients with Parkinson's disease SNC. Mitochondria exposed to highly oxidative environment, and the process of oxidative phosphorylation associated with the production of ROS. Much evidence points to a major role of mitochondrial dysfunction as a basis for the pathogenesis of PD, and in particular, defects of mitochondrial complex-I (complex-I) of the respiratory chain. Complex-I defect may be the most appropriate cause degeneration of neurons in PD by reducing the synthesis of ATP.

         Several epidemiological studies have shown that pesticides and other toxins from the environment that inhibits complex-I is involved in the pathogenesis of sporadic PD. MPTP inhibits complex-I and cause the symptoms of Parkinson's disease in humans and animal models.

        Recent evidence suggests defects in the ubiquitin proteasome system (UPS) and also the role of one protein molecular pathogenesis underlying Parkinson's disease. This idea is supported by the fact that α-synuclein, parkin, and DJ-1 is a genetic disorder, the interplay of UPS and mitochondrial function, which may result in the beginning of the pathways involved in the degeneration of neurons in Parkinson's disease.

 

 

      Aggregation of α-synuclein clearly decreased from complex-I inhibition and aggregation like that could also inhibit proteasomal function or flooding. If inhibition of complex-I is the core of the pathogenesis of PD, then the chain of events triggered by α-synuclein aggregation, increased oxidative stress, and ATP synthesis deficit, all of which can interfere with the normal function of the UPS. UPS will result in inhibition of protein accumulation in addition targeted for degradation, some of which are cytotoxic, which in combination with oxidative danger will surely result in the death of dopaminergic neurons. Parkin, UCH-L1, and DJ1 are involved in maintaining the UPS, while PINK1, along with parkin and DJ1, would regulate the normal function of mitochondria; disease-related mutations in these genes will lead to a bunch of events that started the death of DA neurons. However, this incident path other than cause proteasome inhibition but can also go back and forth disrupt mitochondrial function. This observation leads to a large degree of cross correlation between mitochondrial and UPS, and dysfunction in each or all of the system will lead to a common end point of the degeneration of DA neurons.



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