BIO254:LewyBody

What is a Lewy Body?

A Lewy body is an abnormal aggregation of proteins, including alpha-synuclein, neurofilament, and ubiquitin, found in the neurons of patients with certain neurodegenerative diseases such as Parkinson's disease (PD) and Lewy Body Dementia. Typically, affected neurons contain one Lewy body with two or three bodies per cell occuring rarely. The presence of Lewy bodies in the central nervous system can only be determined posthumously. Lewy bodies were first described in patients with PD by Frederich Heinrich Lewy in 1912, who was also their namesake, however Gibb and Lees provide the best brief description of Lewy bodies in their 1994 text, Movement Disorders, as follows:

    The Lewy body is a neuronal inclusion which
    is always present in areas of neuronal degeneration
    in Parkinson's disease. In its classical
    form in the substantia nigra it consists of a
    central core staining deeply with haematoxylin
    and eosin, surrounded by a body which stains
    less intensely, and then a peripheral halo which
    stains lightly or not at all. This appearance is
    relatively uncommon and more usually Lewy
    bodies have no core. Considerable variation in
    shape occurs, including elongated and serpiginous
    forms, and their appearance depends to
    some degree on their location within the nervous
    system. (The various forms were already
    described by Lewy in 1912).

A Lewy body stained for alpha-synuclein Source:http://feany-lab.bwh.harvard.edu/

History

Frederich Heinrich Lewy

Frederic Heinrich Lewy Source:Holdorff B. 2002

Frederic Heinrich Lewy (1885-1950) was the first person to describe the neuronal inclusion bodies, later renamed Lewy bodies, associated with Parkinson Disease (PD) which also known as paralysis agitans. He recieved his medical degree from the Universities of Berlin and Zurich in 1910. Afterwards he worked at the Neuropsychiatric Laboratory in Munich where he performed morphological assessments of PD through clinical and post-mortem examination of PD patients. It was at this time that he described in detail the neuronal inclusion bodies that later became his namesake. His findings were first published in Max Lewandowsky's Handbook of Neurology in 1912, and later presented to the German Association of Psychiatrists and Neurologists in Breslau in 1913. His findings were also published years later in his opus Tonus und Bewegund (Muscle Tone and Movement) in 1923, however he never seemed to make note of the typical occurrence of the inclusions in the substantia nigra of PD patients. This finding was made years earlier in 1919 by C. Tretiakoff who was the first to ascribe the name "Corps de Lewy" or "Lewy bodies" to the inclusions. Interestingly, Lewy never made any note of Tretiakoff's work or any other work showing the significance of Lewy bodies and the substantia nigra in the pathogenesis of PD.

Interesting facts:

-Lewy worked alongside the likes of several other neuroscience super stars including Emil Kraepelin, Alois Alzheimer, Franz Nissl, and Walter Spielmeyer during the time he worked at the Neuropsychiatric Laboratory.

-Lewy, the son of a Jewish doctor, was dismissed as the director of the Neurological Research Institute and Clinic in Berlin in 1933 by the Nazi Regime.

-After emigrating to the US in 1934, Lewy changed his name to Frederic Henry Lewey.

A figure from Lewy's "Tonus und Bewegung", 1923 showing images of Lewy bodies. (Holdorff B. 2002)

alpha-synuclein

Synucleins were first identified in the Pacific electric ray in 1988 by Maroteaux et al. during an expression screen of cDNA clones from the electric lobe of the ray aganist cholinergic vesicle antisera. Later immunostaining revealed that the protein was localized in presynaptic terminals and the nuclear membrane thus the protein was labeled synuclein. Soon after in 1991, three isoforms of synuclein were found in rat brain and were labeled SYN1, SYN2, and SYN3. Then in 1994, Jakes et al. sequenced 2 human synuclein isoforms purified from cerebral cortex and named them alpha- and beta-synuclein. Around the same time researchers studying amyloid plaques in Alzheimer's diseased (AD) brains isolated an unidentified component from purified plaques. This peptide was named the non-amyloid beta component of AD (NAC) and a precursor to this peptide was soon after discover which was named the NAC precursor (NACP). However, at the time the researchers did not realize that NACP had already been discovered and named alpha-synuclein. Later, alpha-synulcein was also found to be a component of Lewy bodies from patients with Parkinson's disease (PD) and Lewy body dementia (LBD), and in Multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and Hallervorden-Spatz syndrome so that all of these neurodegereative diseases became known as the synucleopathies.

Alpha-synuclein is an abundant CNS protein composed of 140 amino acids. The alpha form of synuclein is the only form capable of aggregating into fibrillar structures in vitro. While beta-synuclein is not localized in Lewy bodies, it may have a role in regulating alpha-synuclein metabolism or aggregation (Hashimoto et al. 2001). The normal function of alpha-synuclein is debatable and largely unknown, but evidence exists suggesting it functions in 1) synaptic plasticity 2) negative regulation of dopamine neurotransmission 3) protection at nerve terminals during injury and 4) trafficking of cargo in the ER/Golgi complex (Lee and Trojanowski, 2006). In sporadic Lewy body diseases, alpha-synuclein is ubiquitinated with no loss of proteasome function, suggesting there is an exessive accumulation of alpha-synuclein that overwhelms the proteolytic machinery (Tofaris, et al. 2003). This may promote the formation of Lewy bodies.

Signs & Symptoms of Lewy Body Disease

The symptoms of Lewy Body Disease (LBD) bear a striking resemblance to Alzheimer's or Parkinson's diseases, but a combination of distinct signs may help neurobiologists to identify a disorder as LBD:

-mental decline demonstrated by reduced alertness and lowered attention spans

-recurrent visual hallucinations, which occur in about 80% of LBD patients--often at night

-poor response to antopsychotic medications (neuroleptics)

-delusions or depression

-sleep disturbances like insomnia and acting out dreams.

Disease States

Parkinson's Disease

Parkinson's Disease (PD) is an unfortunately common neurodegenerative disease characterized by tremor (more pronounced when patient is not concentrating on movement), slowing of voluntary movement, and muscle rigidity and was first described in 1817 by James Parkinson. The pathology of PD involves lesions due to loss of dopaminergic neurons especially in the substantia nigra, and the presence of cytoplasmic Lewy bodies in other neurons also in the substantia nigra. It has been estimated that about 60% of neurons in the substanstia nigra have to be lost for the symptoms to be expressed. Unlike normal aging, the neurons in PD are lost starting from the lateral and and going to the medial region. The most effective current treatment is L-Dopa, which can cross the blood brain barrier as opposed to dopamine. L-Dopa alleviates symptoms but does not help cell loss; therefore it is more effective in treating early stage PD.

Lewy Body Dementia

Lewy Body Dementia (LBD) is a progressive brain disease which involves the accumulation of Lewy bodies throughout various areas of the brain including the cerebral cortex. Unlike Parkinson's disease which has hallmark symptoms, LBD symptoms are highly variable depending on what brain region is affected, although attention and motor deficits are typical. Like Azheimer's diease, there is no cure for LBD and the disease progresses at a faster rate than AD. LBD was first characterized by H.Okazaki in 1961.

Alzheimer's Disease

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common form of dementia. Its symptoms include memory loss, and the inability to learn and make good judgements. The hallmark of AD is the presence of amyloid plaques, dense aggregates of amyloid beta peptides cleaved from the amyloid precursor protein, which are thought to induce neuronal death. There have also been reported cases of AD in which patients also present with symptoms of Lewy Body Dementia and have been termed as the Lewy body variant of AD. However, it is not clear how the two diseases are related.

Hallervorden-Spatz Syndrome

Hallervorden-Spatz Syndrome is a very rare disease typically found in children that involves the degeneration of various brain structures including the substantia nigra. The symptoms are Parkinsonian-like probably due to the similar loss of dopaminergic neurons in the substantia nigra, but mental and emotional retardation also occur. Children with this disease usually live about 10 years after disease-onset. The pathology involves large deposits of iron in the globus pallidus and substantia nigra although the role that this iron abundance plays in the disease is unclear. Interestingly, patients that experience a longer course of the disease usually present with Lewy bodies in the cortical and subcortical brain regions.

References

Bennett MC. 2005. Pharma Therap. 105: 311-331.

Feany Lab Website: http://feany-lab.bwh.harvard.edu/

Hashimoto, et al. (2001). Beta-synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32 213-223.

Holdorff B. 2002. J Hist Neurosci. 11: 19-28.

Lee and Trojanowski. (2006). Mechanisms of Parkinson's Disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron. 52(1) 33-38.

Tofaris, GK, et al. (2003). Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J. Biol Chem. 278(45):44405-11.

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