Understanding Proteins, Understanding Parkinson Disease (PD

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This is also a reposting of something that Bill Werre put in awhile back for those of you new to the group.

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website... Understanding Proteins, Understanding Parkinson

Understanding Proteins, Understanding Parkinson Disease (PD)

by Abraham Lieberman MD Medical Director of the National Parkinson Foundation

PD results from a loss of cells in the substantia nigra. The substantia nigra is part of the brainstem. The loss of cells is confined to pigmented, dopamine-containing cells. These cells, unlike other, near-by dopamine cells lack a specific protein--calmodulin. Calmodulin is involved in calcium-regulation. The role of calmodulin, and the vulnerability of dopamine cells lacking-calmodulin to die prematurely is, at this time, unknown. PD-like diseases, diseases with symptoms like PD, but with a more rapid course, are characterized at autopsy by a more wide-spread loss of dopamine and non-dopamine cells. The dopamine loss includes calmodulin-containing and calmodulin-lacking dopamine cells. The PD-like diseases sometimes called PD-plus diseases, or atypical PD or Parkinson Syndrome include Multiple System Atrophy (MSA), chemically caused Parkinson (Parkinson caused by MPTP or manganese) and Autosomal Recessive (AR), inherited or genetic Juvenile Parkinson. Understanding the relationship of PD to the PD-like diseases is a necessary step to understanding (and curing) PD.

In PD, but not the PD-like diseases, the loss of cells in the brainstem is accompanied by Lewy bodies. Lewy bodies are spherical inclusions present within the cytoplasm (the part of the cell outside the nucleus) of the dying cells. Lewy bodies are large relative to the cell. Lewy bodies, as viewed under the electron-microscope, are composed of a dense-ore of vesicles surrounded by a rim of radiating fibers (called fibrils). Understanding the structure and composition of Lewy bodies is a necessary step to understanding (and curing) PD.

PD affects one million Americans. The majority of PD patients are aged 60+ years. This represents !% of Americans aged 60+ years. In addition, 10% of all 60+ year olds ( 10% of all 60+ year olds without PD) have Lewy bodies in their brainstem. These people, 10% of all 60+ year olds, may be at-risk-for PD. Understanding the relationship of Lewy bodies in PD and in the 10% of 60+ year olds without PD, is a necessary step to understanding PD--and the aging process.

Lewy bodies occur in dopamine and non-dopamine cells outside the brainstem. These cells are found throughout the brain including the cortex: the thinking part of the brain. Lewy bodies occurring in cells in the cortex (cortical cells) differ from Lewy bodies occurring in cells in the brainstem in the size, shape, and the relationship of the Lewy body to the cell’s nucleus.

30% of PD patients develop, in addition to PD, dementia. PD-dementia is characterized by a loss of memory and a marked decline in intellectual and cognitive abilities. At autopsy the cortical and brainstem cells of PD-dementia patients contain Lewy bodies. Lewy bodies also occur in the cortical cells of patients with Diffuse Lewy Body Disease (DLBD). Unlike PD, patients with Diffuse Lewy Body Disease begin with mental symptoms: loss of memory and a decline in intellectual and cognitive abilities. Diffuse Lewy Body Disease is probably a variant of PD: Diffuse Lewy Body Disease is PD beginning with memory loss and a decline in intellectual and cognitive abilities rather than PD beginning with rigidity, tremor, and slowness of movement. In time, if patients live, patients with Diffuse Lewy Body Disease come to resemble patients with PD and vice-versa.

Diffuse Lewy Body Disease, is next to Alzheimer Disease (AD), the most common cause of dementia in 60+ year olds. Lewy bodies are also present in cells in the cortex of AD patients. This disorder, AD with Lewy bodies, is probably a variant of AD and/or Diffuse Lewy Body Disease. Alzheimer Disease, Alzheimer Disease with Lewy bodies, Diffuse Lewy Body Disease, PD with dementia, and PD without dementia are probably a continuum, one disease presenting differently but, in time, coming together. Understanding the relationship of cortical to brainstem Lewy bodies is a necessary step to understanding the relationship of PD to dementia, PD to Diffuse Lewy Body Disease, and PD to AD.

Cortical and brainstem Lewy bodies are associated, to varying degrees, with deposits of 3 proteins: alpha-synuclein, parkin, and ubiquitin. Each protein is produced or manufactured inside the cell’s nucleus. Here, amino-acids (the building-blocks of proteins), are assembled like beads on a string. This sequencing is determined by the person’s genetic code: the information contained on the his or her’s DNA. a person’s DNA is fixed, immovable, inside his or her’s cell’s nucleus. Each gene, made-up of a segment of DNA, writes or transcribes it’s information onto RNA, a moveable molecule. The information written or transcribed onto RNA, is then translated into proteins. Each gene codes for a single protein.

Each person has, approximately, 100,000 genes, entwined, like "steel coils" on 23-paired chromosomes (a total of 46 chromosomes). Each cell, in each person, contains the full complement of 100,000 genes. However, each cell, or group of cells, is programmed to activate only a specific number of it’s 100,000 genes. The specific number of genes activated vary with the cell. Thus brain cells activate a different number of genes than liver cells. This results in brain cells producing different types of proteins than liver cells.

Inside the brain, cortical cells activate a different number of genes than brainstem cells. This results in cortical cells producing different types of proteins than brainstem cells. In the brainstem, dopamine-containing cells activate a different number of genes than non-dopamine cells. This results in dopamine cells producing different types of proteins than non-dopamine cells. And, in dopamine-containing cells, calmodulin-lacking cells (those that die prematurely in PD) activate a different number of genes than calmodulin-containing cells ( those resistant to PD). This results in calmodulin-lacking cells producing a different type of proteins than calmodulin-containing cells. Understanding the differences in the activation of different genes in different cells is essential to understanding PD, PD-dementia, Diffuse Lewy Body Disease, and AD.

All proteins, including alpha-synuclein, parkin, and ubiquitin are made in the nucleus. After they’re made, they’re modified (or shaped) in two regions outside the nucleus: the endoplasmic reticulum and the Golgi-apparatus. The sequencing of amino-acids, the relationship of one amino-acid to the-one-behind-it and the-one-ahead-of-it ( the one-dimensional structure of the protein) is determined by DNA. Genetic defects and/or environmental toxins (or poisons)may change the sequencing of amino-acids in a protein. This, in turn, may change the protein’s function.

The 2-dimensional and 3-dimensional structure of each protein, it’s shape or configuration in space, is determined after it’s amino-acid sequence is laid-down. Environmental toxins, from outside or inside the cells, may change the 2-dimensional or 3-dimensional shape of the protein. This post-translational change may change the protein’s function.

Alpha-synuclein is part of a family of proteins: the synucleins. Alpha-synuclein occurs in a restricted number of brains cells including dopamine-containing cells in the cortex and brainstem. Alpha-synuclein is made inside the cell’s nucleus. Then, after alpha-synuclein’s modified in the endoplastic reticulum and/or the Golgi apparatus, it migrates through a series of hollowed-out, tunnel-like structures or fibrous tubes (called fibrils) to the periphery of the cell. Here, in the periphery, alpha-synuclein is associated with vesicles: small fluid-filled sacs. Alpha-synuclein may be associated with the storage and/or release of dopamine. In PD, an abnormally shaped or configured alpha-synuclein becomes "stuck" in one of the fibrous tubes (or tunnels). This build-up or accumulation of alpha-synuclein is part of the Lewy body.

Alpha-synuclein is part of a family of proteins: the synucleins. Alpha-synuclein occurs in a restricted number of brains cells including dopamine-containing cells in the cortex and brainstem. Alpha-synuclein is made inside the cell’s nucleus. Then, after alpha-synuclein’s modified in the endoplastic reticulum it migrates through a series of hollowed-out, tunnel-like structures or fibrous tubes (called fibrils) to the cell’s periphery. Here, in the periphery, alpha-synuclein is associated with vesicles: small fluid-filled sacs. Alpha-synuclein may be associated with the storage and/or release of dopamine. In PD, an abnormally shaped or configured alpha-synuclein becomes "stuck" in the fibrous tubes (or tunnels). This build-up or accumulation of alpha-synuclein is part of the Lewy body.

Parkin occurs in a restricted number of brains cells including dopamine-containing cells in the cortex and brainstem. Parkin is made inside the cell’s nucleus. Then, after it’s modified in the endoplastic reticulum it migrates through a series of hollowed-out, tunnel-like structures or fibrils. Parkin is probably a scavenger-protein, one that breaks-up abnormal accumulations or clumps of other proteins (like alpha-synuclein). In PD, parkin, like alpha-synuclein, clumps on Lewy bodies. Except in a rare form of Juvenile PD, one occurring in Japan, the accumulation of parkin is a secondary event. The primary event in all probability is the accumulation of alpha-synuclein.

The ubiquitins are a family of proteins found throughout the brain. They’re ubiquitous--hence the name ubiquitin. Ubiquitins account for 2% of all brain proteins. The ubiquitins are made inside the nucleus. Then, they’re modified in the endoplastic reticulum and migrate through the fibrils. The ubiquitins are scavenger proteins. In PD, the ubiquitins, like alpha-synuclein and parkin accumulate and clump on Lewy bodies. Except in a rare form of inherited, genetically-determined PD, the accumulation of ubiquitin is a secondary event. The accumulation probably results from an attempt by ubiquitin to break-up the accumulation of alpha-synuclein.

1% of PD is strictly, or solely, genetically determined. In several American and European families a mutation on chromosome-4 of the gene coding for alpha-synuclein results in PD. These patients develop PD at an early age, below age 40 years. Otherwise their symptoms and response to Sinemet are similar to typical adult-onset PD. At autopsy these patients, like patients with typical PD, exhibit degeneration of dopamine-cells. The degeneration is associated with Lewy bodies. And the Lewy bodies contain deposits of alpha-synuclein, parkin, and ubiquitin. Understanding the relationship of genetically-determined, mutated (or altered) alpha-synuclein and familial to non-familial PD are necessary steps to understanding PD.

In several Japanese families a mutation on chromosome-6 of the gene coding for parkin results in PD. These patients develop PD at an early age, below age 16 years. Otherwise their symptoms and response to Sinemet are similar to typical adult-onset PD. At autopsy these patients, like patients with typical PD, exhibit degeneration of dopamine-cells. Unlike typical PD, the degeneration is unassociated with Lewy bodies. Understanding the relationship of parkin to alpha-synuclein, the relationship of Japanese to American and European PD are necessary steps to understanding PD. The recent availability of genetically-determined animal models will help.

In 15% of PD patients there’s a family history of PD. Their symptoms and response to Sinemet are typical of non-familial PD. At autopsy these patients, like patients with non-familial PD, exhibit degeneration of dopamine-cells. The degeneration is associated with Lewy bodies. And the Lewy bodies contain deposits of alpha-synuclein, parkin, and ubiquitin. Whether their alpha-synuclein is genetically-altered or altered by an environmental toxin is unknown. Understanding the relationship of genetically-altered alpha-synuclein, alpha-synuclein altered before it’s translated from RNA, to environmentally-altered alpha-synuclein, alpha-synuclein altered after it’s been translated is a necessary step to understanding PD.

Multiple System Atrophy (MSA), a PD-like disease, is unassociated with Lewy bodies. Although, initially, the symptoms of MSA may be similar to PD. However, the course (a more rapid progression than PD) and the response to Sinemet (little or no response) is different from PD. However, in MSA alpha-synuclein deposits on inclusions, inside the cytoplasm or nucleus of support (glial) cells as well as nerve cells. These inclusions are smaller and differently shaped than Lewy bodies. Understanding the differences between the inclusions in MSA and Lewy bodies is another step to understanding PD and the PD-like diseases.