ReviewYou say lipofuscin, we say ceroid: Defining autofluorescent storage material
Introduction
The US Census Bureau predicts that there will be at least 30 million people in the 65 and older age bracket, with approximately 5 million US residents over the age of 85 by the year 2010 [110]. This estimated increase in the elderly population is not unique to the United States, but will be felt worldwide. By the year 2050 the United Nations predict globally that one in six people will be over the age of 65 years old, with anticipated population totals of aging individuals around 606 million [81]. As the population continues to age, the drive for an improved standard of living for the elderly and an increase in aging research will continue to rise.
Aging pigment, better known as lipofuscin, is the pigment that accumulates as a normal part of senescence. It has been implicated in numerous age related diseases such as Alzheimer disease, Parkinson disease, heart failure and macular degeneration. Ceroid, lipofuscin-like, is the general term for lipopigment accumulating as a result of a pathological condition. This pigment has also been implicated pathologically such as neurodegenerative diseases, brain lesions, nutritional cirrhosis, Vitamin E deficiency and many other conditions. However, for this review we will focus on a family of childhood neurodegenerative diseases, the neuronal ceroid lipofuscinoses (NCLs). The NCLs have been estimated to have an occurrence of 1 in 12,500 live births [77]. All NCLs have an accumulation of ceroid in the lysosomes of neurons and other cell types as a major pathological hallmark [42]. Lipofuscin has been used over the years to also describe pathological lipopigments arising from age-related diseases and macular degeneration diseases. However, the two terms lipofuscin and ceroid are not sufficient to properly define all autofluorescent storage materials.
Section snippets
Lipofuscin
What is lipofuscin? This “wear and tear” or “aging pigment” is an autofluorescent lipopigment that accumulates in aging cells. The history of the initial observation of lipofuscin and its name derivation was reviewed by Brizzee and Ordy [7]. The first description of this intracellular pigment was by Hannover in 1842, where he observed a pigment in the perikaryon of aging neurons. Lipofuscin was originally coined by Borst, and first appeared in the literature by Hueck in 1912. The term
Ceroid
What is ceroid? Ceroid was originally defined in 1941 as the lipopigment found in rat livers afflicted with nutritional cirrhosis [6]. Ceroid has subsequently been defined as a lipofuscin-like lipopigment that arises from pathological conditions such as disease, malnutrition, and cell stress [116], [129]. This term has been applied to the lipopigment found in lysosomal storage diseases such as the NCLs and Niemann-Pick disease. The NCLs will be used in this review as the example for defining
Lipofuscin fluorophores
Lipofuscin has been shown to have a range of spectral properties, but what does this say about the fluorophores seen in different tissues? Are the same fluorophores being accumulated in all tissues and the variance is due to the lipofuscin being in a different stage of its existence? Alternatively, lipofuscin in different tissues could be exposed to an array of various biochemical processes resulting in the non-degradable autofluorescence substance jointly termed lipofuscin.
For example,
Distinguishing features of lipofuscin and ceroid
So how do we distinguish lipofuscin and ceroid? All the lipopigments that fall under the description of lipofuscin and ceroid were identified and studied for very different reasons. Lipofuscin and ceroid have very similar characteristics, but are they the same lipopigment? Clearly, our previous descriptions of lipofuscin and ceroid indicate they are indeed composed of different materials. In addition, diseases such as Best disease and Stargardt disease, not discussed in this review have storage
Lysosomes
A major lysosomal function is the breakdown and recycling of macromolecules and organelles into basic precursors. Although the lysosome used to be thought of as a common garbage disposal vesicle with unwanted cellular components being trafficking for degradation to this organelle, lysosomal function is much more complex. This organelle contains highly specialized enzymes capable of degrading extracellular and intracellular proteins, organelles, received for degradation from trafficking pathways
Mechanisms of lysosomal dysfunction that can lead to ceroid accumulation
Lipofuscin and ceroid accumulate in the lysosome. We propose four possible mechanisms of lysosomal dysfunction that could result in accumulation of autofluorescent lysosomal storage material in a pathological condition. First, a missing or defective enzyme can result in a block in a biochemical pathway, terminating the associated biochemical process and precipitating the accumulation of the enzyme substrates that either have inherent autofluorescence or in aggregate with other lysosomal
Ceroid in the NCLs
For NCLs, defects in six proteins have been identified to be associated with the six distinct NCL-disease variants. Only two of these proteins are considered to have known function. The other four proteins are membrane proteins of unknown function. Infantile neuronal ceroid lipofuscinosis results from a mutation in the CLN1 gene that encodes palmitoyl protein thioesterase, PPT1 [55], [56], [122]. PPT1 is a lysosomal long chain fatty-acid hydrolase, which removes fatty acyl groups from S
Lysosomal function
Does accumulation of lipopigments compromise lysosomal function? Many studies, particularly on lysosomal enzyme activity have addressed this question, with conflicting conclusions. For example, a decrease in lysosomal cysteine protease activity was associated with increased lipopigment accumulation in human fibroblasts and rat neurons [2], [43]. A potentially conflicting study showed that expression of cathepsin B, an lysosomal cysteine protease, in aging rat liver was increased [62]. In aging
Autophagy
Another possible mechanism for the accumulation of lipopigments would be a disturbance in the process of transporting macromolecules and organelles to the lysosome. Degradation of cytosolic components in the cell by lysosomes is termed autophagy. The autophagic process can be broken down into two basic steps: (1) delivery of components for degradation to the lysosome and (2) degradation of components in the lysosome by proteases. In normal functioning cells, degradation of material, once in the
Oxidation
In 1956, Harman proposed the free radical theory of aging in which he stated that an oxygen radical such as hydroxyl (OH) and reactive oxygen species like hydrogen peroxide (H2O2) that emanate from respiratory processes result in the oxidation seen in aging and degenerative disease. Many studies on this topic are reviewed in [49]. Lysosomes can take up, store, and degrade ferritin so that the cell can extract the iron to reutilize it in the cell [94]. The presence of iron in lipopigment could
So what is the mechanism of lipofuscin and ceroid accumulation?
Both lipofuscin and ceroid appear to be similar biochemically. However, variation in the constituents of ceroid within the NCLs alone suggests that autofluorescent lipopigment may come in many forms. Therefore, if the composition of lipopigment varies, it is likely that the mechanism of accumulation of lipofuscin and ceroid could also be different. A summary of the possible mechanisms of lipopigment accumulation is illustrated in Fig. 1. Accumulation of lipofuscin and ceroid can likely be
Concluding remarks
Lipofuscin and ceroid are lipopigments with some similar biochemical properties. However, lipofuscin and ceroid are composed differently and based on our understanding of the biology involved it is likely that many cellular disturbances could lead to accumulation of lipopigments that could be termed lipofuscin-like or ceroid-like. Cells or in particular lysosomes that have evidence of accumulating lipopigments such as lipofuscin or ceroid exhibit evidence of altered biochemical function that
Acknowledgements
The authors wish to thank Jared Benedict for help in preparing Fig. 1, and Lindsay Burwell for useful comments in preparation of the manuscript. Supported by NIH NS036610 and NS044310.
Conflicts of interest: The authors have no conflicts of interest or financial disclosures.
References (130)
- et al.
Effects on in vivo and in vitro administration of vinblastine on the perfused rat liver—identification of crinosomes
Exp Mol Pathol
(1987) - et al.
Age-related changes in cellular localization and enzymatic activities of cathepsins B, L and D in the rat trigeminal ganglion neuron
Mech Ageing Dev
(1995) - et al.
Mitochondria, oxidants, and aging
Cell
(2005) - et al.
Immunoreactivity of neuronal lipofuscin with monoclonal antibodies to the amyloid beta-protein
Neurobiol Aging
(1989) - et al.
Biosynthetic studies of A2E, a major fluorophore of retinal pigment epithelial lipofuscin
J Biol Chem
(2002) Lipofuscin
Prog Brain Res
(1973)- et al.
Lipofuscin: mechanisms of age-related accumulation and influence on cell function
Free Radic Biol Med
(2002) - et al.
The yeast model for Batten disease: a role for Btn2p in the trafficking of the Golgi-associated vesicular targeting protein, Yif1p
Biochem Biophys Res Commun
(2003) - et al.
Lysine 43 is trimethylated in subunit C from bovine mitochondrial ATP synthase and in storage bodies associated with batten disease
J Biol Chem
(2004) - et al.
When lysosomes get old
Exp Gerontol
(2000)