El Premio Nobel en Química 1972

Christian B. Anfinsen

Stanford Moore

William H. Stein
Proteasa dependiente de ATP

El proteosoma contiene
receptores para ubiquitina

Ubiquitina
- 76 aa
- Estructura primaria muy conservada
- Se asocia a residuos de Lys
 Proteins with chains of at least 4 ubiquitins are the
preferred substrates of the proteasome

But some proteins do not require ubiquitination to

be degraded by the proteasome, although the
relevance of this process in vivo is still unclear

And ubiquitination can also target substrates

for degradation by autophagy

The ubiquitin–proteasome system (UPS), which usually degrades

the majority of proteins, and autophagy, primarily responsible for
the degradation of most long-lived or aggregated proteins and
cellular organelles. Disruption of these processes can contribute
to pathology of a variety of diseases.
Most misfolded soluble proteins would be preferentially degraded by the proteasome, and by autophagy only if the
proteasome capacity is exceeded. However, micro- and macroautophagy are both able to degrade soluble proteins,
either on a housekeeping basis, or as a bulky process under stress in the case of macroautophagy, as it is the case
under amino acid, energy, or growth factor depletion. However, aggregates can only be degraded by autophagy.

Cells respond to blockage of the UPS by up-regulating macroautophagy, whereas persistent blockage of macroautophagy
has been shown to compromise UPS activity.
Secuencias PEST
(Pro - Glu -Ser – Thr)
Given the intrinsic propensity of
proteins to aggregate, it is not
surprising that we are endowed
with a powerful array of defense
mechanisms whose role is to
preserve protein homeostasis by
helping to maintain proteins in
their soluble states and to
promote the degradation of those
that misfold and aggregate.
The progressive decline of the
efficacy of the regulatory
processes upon aging is likely to
contribute to the increased
susceptibility of the elderly
population to age-associated
neurodegenerative disorders.
 Premio Nobel en Fisiología / Medicina 1997

Por su descubrimiento de los

"priones - un nuevo principio
biológico de infección"

Stanley B. Prusiner
 Enfermedades neurodegenerativas en mamíferos

Aislamiento de los priones como

causantes de la enfermedad

Ovejas con
Scrapie

La más conocida:
encefalopatía espongiforme bovina
(“enfermedad de las vacas locas”)
Enfermedad de Kuru
 Diferencia

“Infecciosa”

Si es ingerida por un Los priones transmiten

huésped susceptible la “infección”
 Rol de APP:
algunos experimentos indican que los fragmentos de APP
participarían en el transporte axonal, adhesión celular, sobrevivencia
celular, metabolismo del colesterol y transcripción génica.
 Many studies suggest that Aβ might have a
physiological function, such as synaptic signaling. In
fact, Aβ peptide can be detected in human
cerebrospinal fluid. Typically, in healthy individuals,
the predominant form of Aβ is Aβ1–40 (about 90% of
the total amount) while Aβ1–42 represents
approximately a 10% fraction. This ratio is
dramatically altered in AD

β-secretase has optimal activity at a pH of ~4.0. The enzyme is

usually located on the cell surface where the ambient pH is
much higher (~7) forcing it to remain dormant. The
proteolysis of APP by β-secretase necessitates internalization
of both molecules through an endocytic mechanism into
lysosomes.
At more optimal pH, β-secretase then cleaves APP and these
intracellular sites become the major locations for the
production of Aβ
Under normal conditions, Ab is either relocated, or
degraded, or secreted extracellularly (mayoritary). The
fact that lysosomes showed little Aβ immunoreactivity
would suggest that cells are able to perform a rapid
proteolytic digestion of this peptide under normal
biological conditions.
It is suggested that impaired Aβ secretion and resulting
intraneuronal increase of Aβ can contribute to AD
pathology. However, it is not clear how Aβ is distributed
inside normal neurons, and how this distribution is
afected when Aβ secretion is inhibited.
 It has also been suggested that an over
accumulation of Aβ1–42 inside the neuron
causes lysis and amyloid plaques represent the
sites where this happens.

Amyloid plaques are not simple structures composed of

a single molecular population (ie, Amyloid β). In fact, a
variety of substances have been found in these lesions.
These include: proteoglycans (heparan, chondroitin,
keratin, dermatan sulphate), inflammatory molecules,
cytokines, chemokines, complement proteins, serum
related molecules, metal ions, non-Aβ component of
AD, apolipoprotein E, etc.
 Researchers found that the
deadly connection between Ab
and tau, occurs before they form
plaques and tangles.
 Huntington’s Disease is caused by a gene
mutation that creates excess copies of the CAG
(Gln) codon which genetically program the
degeneration of the neurons of the brain.

 It is an Autosomal Dominant disease which

affects muscle coordination and some cognitive
functions. The onset is found generally in
adults around the age of 40

 The number of CAG codons varies and so does

the severity of the disease
 •Huntington’s is caused by a mutated Chromosome 4

• Huntingtin gene (HTT), which codes for the protein huntingtin

(HTT; mutated: mHTT)
• More than 36 CAG repeats (Gln)

La función de HTT no ha sido claramente definida, pero existen evidencias de su interacción con
numerosas proteínas involucradas en la expresión génica, transporte intracelular, transducción de
señales, apoptosis y función mitocondrial.

mHTT es tóxica en ciertos tipos celulares, particularmente el cerebro

Las imágenes y fotografías contenidas en este ppt fueron obtenidas de libros o
en internet, con el único propósito de generar esta presentación para uso
netamente académico